Download Treatment of Patients with Refractory Giardiasis

MAJOR ARTICLE
Treatment of Patients with Refractory Giardiasis
Theodore E. Nash,1 Christopher A. Ohl,2 Elaine Thomas,3 Gangadnaran Subramanian,1,a Paul Keiser,1
and Thomas A. Moore4
1
Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;
Infectious Disease Section, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina; 3Department
of Medicine, University of New Mexico, Albuquerque; and 4Department of Internal Medicine, School of Medicine, University of Kansas, Wichita
2
Giardia lamblia is one of the most common parasitic infections. Although standard treatments are usually
curative, some immunocompromised patients, including patients with acquired immunodeficiency syndrome
as well as healthy patients, have giardiasis that is refractory to recommended regimens. We report our experience with 6 patients with giardiasis, for whom therapy with a combination of quinacrine and metronidazole
resulted in cures for 5 of the 6 patients.
Received 13 September 2000; revised 30 October 2000; electronically published
23 May 2001.
Approved informed consent was obtained and clinical research conducted in
accordance with guidelines for human experimentation as specified by the US
Department of Health and Human Services, Washington, DC.
a
Present affiliation: Celera Genomics, Rockville, Maryland.
Reprints or correspondence: Dr. Theodore Nash, National Institutes of Health,
9000 Rockville Pike, Bldg. 4, Room B1-01, Bethesda, MD 20892.
Clinical Infectious Diseases 2001; 33:22–8
2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3301-0004$03.00
22 • CID 2001:33 (1 July) • Nash et al.
tients, such as those with common variable hypogammaglobulinemia [10–12] and those with lymphoproliferative diseases that involve the gastrointestinal tract
[13–15], seem abnormally susceptible to giardiasis, and
their infections are frequently difficult to cure. Although patients with HIV infection and AIDS can usually be successfully treated [16], some of these patients
develop life-threatening giardiasis and do not respond
to usual therapies [17]. Reinfection is common in
regions where infection is highly endemic and where
environmental contamination is high [18]. In developed countries, where the prevalence of infection is low
and exposure is infrequent, reinfection is not frequently
a cause of treatment failure. Patients who experience
abnormal pharmacokinetics or who are infected with
organisms that are resistant to treatment are rarely documented. Exactly what pharmacological factors are important in the successful treatment of patients with giardiasis has not been determined.
Patients who do not respond to treatment usually
receive multiple courses of standard drugs; frequently,
the duration of treatment is increased, the dose is increased, or both. In the United States, these drugs most
frequently are metronidazole and furazolidone. Quinacrine is no longer routinely available, but it can be
obtained from a pharmacy that formulates its own stock
(e.g., Panorama Pharmacy). Tinidazole is commonly
used in regions other than the United States. For infections that are refractory to these agents, other treat-
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Giardia lamblia is the most common gastrointestinal parasite in the United States and in most developed countries [1, 2]. It is the cause of both epidemic and endemic
diarrhea and upset of the gastrointestinal system. There
are a number of drugs whose efficacies are well studied
and that have been accepted for the treatment of patients
with this infection. The published rates of cure vary for
different regimens, but they are frequently reported to
be 190% [1, 3–7]. Nevertheless, some individuals experience treatment failure, despite having received successive courses of treatment that have been documented
to result in a cure for most patients.
There are 6 potential causes of treatment failures:
reinfection, inadequate drug levels, immunosuppression, resistance to the drug, sequestration in the gallbladder or pancreatic ducts, and unknown reasons. In
the normal clinical situation, the presence of immunosuppression, reinfection, or sequestration [8, 9] can
usually be determined. Certain immunosuppressed pa-
ment options include drugs with known in vitro activity but
with no or limited information on in vivo efficacy.
We have advised, consulted, and cared for an increasing
number of patients infected with Giardia that are unresponsive
to the usual suggested medical treatments, and we report our
experience. The findings of the patients who comprise the case
report are summarized in table 1.
CASE REPORTS
Table 1.
Patient
Histories of patients with refractory giardiasis.
Underlying disease
Duration of
giardiasis
1
None
2
Common variable
hypogammaglobulinemia
1.5 years
6 months
3
AIDS
4 yearsa
4
AIDS
15 months
5
Complex immunodeficiency
1.5 years
6
Noneb
8 months
Unsuccessful
treatment
Successful
treatment
Duration of
follow-up
Mtz, T, T/Dox
Q/Mtz
2 years
Mtz
Q/Mtz
10 months
Mtz, T, Pm, A, Dox
Pm/F, T/Q, B/Pm
20 months
Mtz, F, Pm, A
Q/Mtz
2 months
Mtz
Q/Mtz
2 months
Mtz, F
Q/Mtz
2 months
NOTE. A, albendazole; B, bacitracin; Dox, doxycycline; F, furazolidone; mo. month; Mtz, metronidazole; Pm, paromomycin;
Q, quinacrine; T, tinidazole.
a
b
Infection recurred during the 4-year period.
Subsequently received a diagnosis of and died of cancer.
Refractory Giardiasis • CID 2001:33 (1 July) • 23
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Patient 1. A 47-year-old woman was referred to the National
Institutes of Health (NIH) for giardiasis that was unresponsive
to standard treatments. In January 1995, the patient complained
of belching, nausea, bloating, abdominal distention and discomfort, and occasional loose stools. The results of an extensive
evaluation were initially negative, but repeated esophagogastroduodenoscopy performed in July 1995 revealed Giardia trophozoites in duodenal biopsy specimens. The patient received
metronidazole, 250 mg given t.i.d. for 2 weeks, which resulted
in transient improvement of symptoms, followed by treatment
for 6 weeks. After the patient received such treatment, Giardia
trophozoites were still present in duodenal biopsy specimens.
In July 1996, she was treated with oral metronidazole, 750 mg
given b.i.d. for 4 weeks, followed by 500 mg given b.i.d. for 2
weeks, which resulted in a decrease in the frequency of belching;
however, other symptoms persisted, and duodenal samples that
were obtained during therapy again demonstrated Giardia trophozoites. After the patient discontinued therapy, her original
symptoms returned. She was referred to the NIH for further
evaluation and treatment.
The patient and her husband denied having known risk factors for giardiasis, and her history did not suggest the presence
of immunodeficiency. The findings of HIV serological testing,
tests for quantitative serum levels of immunoglobulin, IgG subclasses, and serum levels of protein, and immunoelectrophoresis were unremarkable. Subsequently, the patient underwent
2 sequential treatment regimens that consisted of tinidazole, 2
g given once followed by 500 mg given q.d. for 14 days, followed
by a combination of tinidazole, 500 mg given q.d., and doxycycline, 100 mg given b.i.d., for 21 days. Before the commencement of each treatment regimen, stool samples tested
positive for Giardia by means of EIA and stool examinations,
but they became negative during therapy, only to revert to
positive after the treatments. Transient improvement of symptoms was noted during treatment. A 21-day course of combination therapy with oral quinacrine, 100 mg given t.i.d., and
oral metronidazole, 250 mg given t.i.d., resulted in the following
drug-related side effects: mild headache, dizziness, and subtle
yellow discoloration of the skin. Stool samples obtained immediately before the commencement of treatment again demonstrated the presence of Giardia, according to EIA, but they
became negative for Giardia both during treatment and for 3
months after completion of therapy, according to both microscopic examination and EIA. Successive esophagogastroduodenoscopy and examination of duodenal biopsy specimens
found no evidence of Giardia or of histopathologic abnormalities. Although there was moderate improvement in symptoms, some epigastric discomfort remained but responded to
empirical treatment with omeprazole. The patient has remained
healthy for the past 2 years.
Patient 2. A 46-year-old woman had common variable hypogammaglobulinemia diagnosed in 1987 after she experienced
repeated bouts of sinusitis. In August 1990, the patient was evaluated at the NIH for nausea and intermittent loose stools that
began 2 months prior to evaluation, after she went on a canoe
trip. Stool samples that were assessed for ova and parasites tested
positive for Giardia cysts, and she received metronidazole, 250
mg given b.i.d. for 2 weeks. At the time of this admission to the
hospital, she also had lactose intolerance, sinusitis, and pernicious
anemia diagnosed. Stool samples assessed for ova and parasites
subsequently tested positive twice for Giardia cysts, and in February 1991, she received a 2-week course of metronidazole, 500
24 • CID 2001:33 (1 July) • Nash et al.
abnormalities. Because of concerns about hepatotoxicity from
quinacrine-tinidazole, the patient received albendazole, 400 mg
given q.d., and was advised to eat tofu and to avoid dairy products. Tofu was suggested because it contains the isoflavone formonomentin, a compound with in vitro and in vivo activity
against Giardia [19]. His symptoms improved and became tolerable, but he continued to have 3–4 loose stools per day, and
stool specimens continued to test positive for Giardia.
In July 1999, the patient was admitted for an opportunistic
fungal infection of the sinuses. During this period of hospitalization, he developed progressive weight loss due to multiple
factors, and a more satisfactory treatment of his giardiasis became a priority. A regimen of orally administered bacitracin
capsules, 120,000 U given every 12 h, and paromomycin, 500
mg given b.i.d., was chosen because these are luminal agents
with anti–Giardia activity, and they would likely not interfere
with the medications that he was taking. His diarrhea resolved
within a few days, and the results of microscopic examination
and of EIA of his stool samples became negative for Giardia.
This regimen was continued for 3 months. He reported no side
effects, having 1–2 soft stools per day. Approximately 11
months after discontinuation of the paromomycin and bacitracin, he continues to be relatively asymptomatic, and the
results of microscopic evaluation and EIA of his stool samples
have remained repeatedly negative for Giardia. His CD4 cell
count, which was 15 cells/mL at the time that bacitracin and
paromomycin were discontinued, has increased to 1100 cells/
mL, perhaps because of increased absorption of his highly active
antiretroviral therapy (HAART) regimen.
Patient 4. A 39-year-old man, who had HIV infection
diagnosed in 1988, had AIDS and a CD4 cell count of 24 cells/
mL. He had a history of resolved giardiasis in April 1995. He
had giardiasis diagnosed in February 1996 after a camping trip,
and he was treated with multiple courses of metronidazole
because of recurrent symptoms and repeatedly positive results
of EIAs and examinations of stool samples. In May 1996, the
patient’s stool samples were still testing positive, and he received
a suboptimal dose of oral furazolidone, 100 mg given q.d. for
10 days. Results of EIAs of stool samples were again positive
in August 1996, and he received a correct dose of furazolidone,
100 mg given q.i.d. for 10 days, with some improvement of
symptoms. In November 1996, he had increased diarrhea, and
giardiasis was again diagnosed on the basis of positive results
of EIA and microscopy. Treatment with oral metronidazole,
250 mg given t.i.d. for 10 days, resulted in stool samples that
tested negative by microscopy but positive by EIA; a 20-day
course of metronidazole resulted in slight improvement of
symptoms, but stool samples again tested positive for Giardia
in January 1997. He received oral albendazole, 400 mg given
q.d. for 14 days, and had a questionable symptomatic response,
but 1 month later, the results of EIAs of stool samples remained
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mg given b.i.d., and quinacrine, 100 mg given t.i.d. Two months
after the patient completed therapy, she complained of watery
diarrhea, which she had experienced for 3 days. Stool samples
tested negative for Giardia 2 times, but Campylobacter coli was
detected. She was treated with erythromycin; afterward, her stool
samples still tested positive for C. coli, so she began therapy with
amoxicillin-clavulanate.
Patient 3. A 41-year-old white man with AIDS developed
intestinal giardiasis in 1995 after a trip to Mexico and southern
California, at which time his CD4 cell count was 4 cells/mL.
He was treated with metronidazole for 2 weeks, but stool samples still tested positive for Giardia cysts. Subsequent treatment
regimens that involved tinidazole, paromomycin, and albendazole were also unsuccessful. He was later successfully treated
with paromomycin and furazolidone; therapy with paromomycin, which was used as a single agent, was continued for a
total of 6 months. Giardiasis developed again in March 1998,
∼1 year after paromomycin therapy was discontinued. The patient received metronidazole, 500 mg given t.i.d. for 2 weeks,
which resulted in some improvement in symptoms; however,
the results of EIAs of stool samples remained positive for Giardia. After a 2-week course of tinidazole, 2 g given q.d., and
quinacrine, 100 mg given t.i.d., his symptoms resolved and the
results of EIA of his stool samples became negative for Giardia.
In June 1998, the patient developed intestinal microsporidiosis
due to Encephalitozoon intestinalis and was administered albendazole, 400 mg given b.i.d. for 3 weeks. Giardia appeared in his
stool samples during this period, accompanied by bloating and
worsening diarrhea. Quinacrine, 100 mg given b.i.d., was added
to the patient’s treatment regimen. Because there was no relief
after a week of treatment, and because microsporidia disappeared
from his stool, albendazole was discontinued and the
anti–Giardia regimen was changed to quinacrine, 100 mg given
b.i.d., doxycycline, 100 mg given b.i.d., and atorvastatin, 10 mg
given q.d. After another week without relief, he began receiving
a 3-week course of quinacrine, 100 mg given t.i.d., and tinidazole,
2 g given q.d. His symptoms improved, and the results of stool
examinations became negative for Giardia.
A week after the patient completed this course of therapy (in
late October 1998), his transaminase levels were found to be
elevated. Alanine aminotransferase levels reached a peak of 871
U/L, which necessitated discontinuation of antiretroviral therapy.
When giardiasis recurred in February 1999, quinacrine-tinidazole
was given in the previously successful dosages; the patient experienced relief of symptoms, and the results of stool examinations became negative after treatment. At follow-up, transaminase levels were again found to be elevated: the alanine
aminotransferase levels reached a peak of 1413 U/L, and antiretroviral therapy was again discontinued. Giardiasis recurred in
April 1999. A 99mTc-N-substituted-2-6-dimethylphenylcarbamoylethy iminodiacetic acid (i.e., HIDA) scan did not reveal any
therapy was begun, and the dosages of metronidazole and quinacrine were increased to 500 mg given t.i.d. and 100 mg given
t.i.d., respectively. This treatment regimen was continued for 5
weeks, and on at least 2 occasions after the discontinuation of
therapy, the results of EIAs for Giardia antigen and of stool
assessments for ova and parasites were negative. Cultures of
stool samples again yielded C. jejuni, but the organism was
eradicated with a course of ciprofloxacin.
Patient 6. A 48-year-old man was healthy until August 1996,
when he developed fever, epigastric pain, bloating, diarrhea, and
dehydration ∼6 weeks after a camping trip. Giardia was the only
pathogen identified, and he was treated with a bolus of iv metronidazole followed by a 5-day course of orally administered
metronidazole. Although his symptoms improved, he still complained of having 3–4 diarrheal stools per day, epigastric discomfort, and tenderness. Giardia trophozoites and cysts were
detected during an examination of stool samples. He was again
treated with oral metronidazole, 250 mg given t.i.d. for 10 days,
and although there was some initial improvement in symptoms,
the symptoms returned after the cessation of treatment, and
Giardia was again detected in an examination of stool samples.
By March 1997, the patient had lost 13.4 kg (29.7 pounds) and
had continuing epigastric pain and diarrhea. Another 10-day
course of metronidazole led to no improvement of symptoms.
Upper endoscopy revealed chronic duodenitis, many Giardia trophozoites, and mild gastric fibrosis. Colonoscopy revealed proctitis. His symptoms continued after he received a 10-day course
of furazolidone, 100 mg given t.i.d., and examinations of stool
samples continued to show Giardia trophozoites. Quantitative
levels of immunoglobulins were normal and the results of HIV
serological tests were negative. Stool samples tested negative for
bacterial pathogens and other gastrointestinal parasites. There
was no activity or source that was suggestive of repeated exposure
to Giardia. In May 1997, the patient commenced a 21-day course
of therapy with metronidazole, 750 mg given t.i.d., and quinacrine, 100 mg given t.i.d. On the last day of combined therapy,
the patient experienced a seizure that was possibly related to this
treatment. The patient’s abdominal symptoms resolved, and the
results of 6 stool examinations for ova and parasites and of 1
EIA for Giardia, all of which were performed during a 2-month
period, were negative.
DISCUSSION
These 6 patients represent a diverse group of immunocompetent and immunocompromised patients whose infections
were not cured after they received standard courses of therapy
for giardiasis. Patient 5 displayed features of both humoral and
cellular deficiency, and patient 2 had common variable hypogammaglobulinemia diagnosed. Patients 1 and 6 had no defined
immunodeficiency.
Refractory Giardiasis • CID 2001:33 (1 July) • 25
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positive; he was then given oral paromomycin, 500 mg given
t.i.d. for 10 days. Again, symptoms improved, but giardiasis
recurred after treatment was stopped. In May 1997, he received
a 21-day course of oral metronidazole, 750 mg given t.i.d., and
oral quinacrine, 100 mg given t.i.d.. During this time, he had
Pneumocystis carinii pneumonia, disseminated Mycobacterium
avium infection, and ileus.
By July 1997, diarrhea had resolved and the patient was
gaining weight after a 8.8-kg (19.5-lb) weight loss. Results of
EIAs of stool samples were negative in May 1997 and July 1997.
Despite having received various regimens of HAART, the patient’s CD4 cell count was 7 cells/mL, and the plasma level of
HIV RNA, was repeatedly 50,000–100,000 copies/mL during
this time, which suggests that immune reconstitution was not
responsible for curing his giardiasis. Although reinfection cannot entirely be eliminated as a cause, several possible sources
of infection were investigated and ruled out.
Patient 5. A 30-year-old man was referred to the NIH for
evaluation of an immunodeficiency syndrome associated with
hypogammaglobulinemia, CD4 cell lymphopenia, cytomegalovirus (CMV) colitis, and giardiasis. The patient was healthy until
1.5 years prior to the time of admission to the hospital, when
he developed an upper respiratory illness followed by diarrhea
(8–10 watery stools per day) and weight loss of 16.8 kg (37.4
lb). Two to 3 months prior to admission to the hospital, he had
undergone evaluation elsewhere that revealed hypogammaglobulinemia, a depressed CD4 cell count, CMV colitis, and giardiasis.
Laboratory studies revealed a CD4 count of 208 cells/mL, hypogammaglobulinemia with an IgG level of 170 mg/dL, an IgM
level of 19 mg/dL, and a nondetectable IgA level. Further studies,
including assessment of lymph node, bone marrow, and intestinal
biopsy specimens, did not reveal the causes of his immunosuppression. The results of HIV serological tests were repeatedly
negative, and cultures of stool samples failed to reveal other
pathogens. He was initially treated with metronidazole, 250 mg
given q.i.d., for an extended but unclear duration; this treatment
failed to eradicate the parasite, although it did result in some
improvement in his gastrointestinal symptoms.
After further evaluations, the patient began receiving treatment with ganciclovir, iv immunoglobulin, and another course
of metronidazole, 250 mg given q.i.d. His condition improved
while he followed this regimen, with considerable weight gain
and only 3 formed stools a day. Evaluation at the NIH, conducted after the patient had followed the aforementioned regimen for ∼10 weeks, revealed stool samples that tested negative
for ova and parasites but positive for Giardia antigen by means
of EIA. He complained of intermittent diarrhea. Campylobacter
jejuni was isolated from stool samples, and colonoscopy revealed aphthous ulcers and colitis of the rectum, sigmoid cecum, and marked ileitis with only rare CMV-positive cells in
the colon. Ganciclovir therapy was discontinued, erythromycin
26 • CID 2001:33 (1 July) • Nash et al.
for complications, including interaction with various drugs and
the formulation of quinacrine, which may have changed. Liver
function abnormalities and seizures are described in association
with quinacrine therapy [31, 32], but they are rarely associated
with nitroimidazole (metronidazole or tinidazole) therapy. Peripheral neuropathy is limiting in longer-term treatment with
nitroimidazoles; encephalopathy, convulsions, and liver failure
are unusual but reported complications of nitroimidazole therapy [33–35]. Our experience with dosing and duration of treatment is limited, and the lowest effective dose and duration have
not been defined.
Other potentially useful drugs were used in this series. Albendazole has known in vitro [36, 37] and in vivo [38–40]
efficacy in the treatment of patients with giardiasis. However,
although at times symptoms were suppressed and the results
of microscopic examination of stool samples reverted to negative, effects were transient, and no patients were cured by this
drug. Other drugs with known in vitro efficacy (including doxycycline [41]; 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors [42], such as atorvastatin; and formonomentin,
an isoflavone found in such legumes as soybeans, that has
significant in vitro and modest in vivo activity) were tried without obvious effectiveness [19, 43]. According to patient 3, eating
fresh tofu appeared to alleviate his symptoms modestly. At the
present time, there are no studies to indicate whether frequently
used drugs, such as HMG CoA reductase inhibitors or foods
that contain compounds with anti-Giardia activity (e.g., tofu),
alter the course or the intensity of infection. Table 2 lists a
number of drugs that are possibly useful for the management
of refractory giardiasis.
The use of bacitracin and paromomycin, the regimen used
to cure patient 3, is based on the clinical and experimental
studies of Andrews et al. [45], who used bacitracin or Zn bacitracin (with or without neomycin) and achieved rates of cure
of 87%–94%. We used paromomycin, an aminoglycoside that
is more frequently employed in the treatment of patients with
giardiasis, as a substitute for neomycin [44]. The regimen that
we used may be particularly useful for patients with infections
that are refractory to treatment and for pregnant patients, for
whom nonabsorbed drugs are preferred. The usefulness of bacitracin alone was not evaluated.
The in vitro drug susceptibilities of Giardia that were isolated
from patients who are refractory to treatment have been evaluated in only a few instances [28, 53, 54]. The methods for
testing drug susceptibilities are not standardized. The isolated
trophozoites of one patient, whose infection was unresponsive
to metronidazole or quinacrine but was cured after administration of combined therapy, showed additive effects in vitro.
The putative resistant isolate had drug susceptibilities that were
similar to those of other isolates [28]. In the second instance,
one isolate was almost 10 times less sensitive to metronidazole
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Patients with AIDS represented the third type of immunocompromised patient with refractory giardiasis in our series.
Giardia infections are relatively common in homosexual populations, but severe infections that are resistant to treatment
have rarely been mentioned [16]. However, 2 recent reports
suggest that giardiasis in patients with AIDS may be more severe
and frequent than was previously thought [20, 21]. Although
HIV-infected patients who are infected with Giardia can normally be treated successfully, there appears to be a subgroup
of patients with low CD4 counts who develop severe and sometimes life-threatening disease and who are difficult to treat and
cure [17]. We have recently been consulted regarding the care
of an additional 5 patients with AIDS whose infections were
unresponsive to usual therapies. Exactly how these patients
differ from most patients with AIDS is unclear. Although B cell
dysfunction has traditionally been thought to increase both
susceptibility to infection with Giardia and the rate of treatment
failure [22], more recent evidence indicates that T cells may
be important. T cells were required to control infections with
Giardia lamblia in an adult mouse model [23], and evidence
suggests that T cell dysfunction occurs in patients with common
variable hypogammaglobulinemia [15, 24–26].
All 6 of the patients we have discussed were treated with
metronidazole or tinidazole in combination with quinacrine,
and this regimen resulted in cure for 5 of the 6 patients; in the
sixth patient (patient 3), the infection was temporarily eradicated. The use of this combination of drugs for management
of giardiasis was previously documented in 2 case reports, each
of which described a patient who had giardiasis that was refractory to multiple courses of metronidazole or quinacrine
and who was cured by use of both drugs in combination [27,
28]. In vitro studies performed in the initial study did not show
in vitro resistance to either of the drugs but did show additive
effects when both drugs were combined [28]. The present report supports the effectiveness of this combination for management of giardiasis that is refractory to standard treatments.
Quinacrine alone was not tried, so its usefulness in refractory
cases is unclear. Previous experience with use of this drug as
a single agent was associated with significant rates of treatment
failure [29]. We suggest that the metronidazole-quinacrine
combination is the most likely to result in the eradication of
Giardia in refractory cases.
Our impression, which is based on use of this combination
since our previous report was published [28], is that the combination was as safe as the single agents used alone. However,
a number of possible troublesome side effects were possibly
related to this therapy in the present series, including significant
liver function abnormalities in one patient and seizure in another. We are aware of 2 episodes of transient psychoses, a
known complication of quinacrine [30], in others who received
the combined regimen. There are a number of possible reasons
Table 2. Selected partial list of possible alternative
drugs for the treatment of patients with refractory
giardiasis.
Drug
In vivo efficacy (host)
or in vitro susceptibility
Reference
Paromomycin
In vivo (human)
[44]
Albendazole
In vivo (human)
[38, 39]
Bacitracin
In vivo (human)
[45]
Neomycin
In vivo (human)
[45]
DL-propanolol
In vivo (human)?,
D-propanolol in vitro
[46, 47]
Niridazole
In vivo (mouse)
[48]
Nitrofurantoin
In vivo (mouse)
[48]
Disulfiram
In vivo (mouse)
[49]
Formonomentin
In vivo (mouse)
[19]
Fenbendazole
In vivo (dog, calves)
[50, 51]
Doxycycline
In vitro
[41]
Monensin sodium
In vitro
[52]
Atorvastatin
In vitro
[42]
was observed in some of our patients, other gastrointestinal
diseases may mimic giardiasis, and infections with Giardia are
common enough to be present when other processes are causing symptoms. When giardiasis is responsible for symptoms
and effective therapy is initiated, improvement in symptoms,
cessation of cyst excretion, negative results of stool antigen
assays by EIA are commonly found.
Acknowledgment
We thank Ms. Sheryl Rathke for editorial assistance.
than was the most sensitive isolate, and the authors briefly
mention, without supporting documentation, that this patient
experienced failure to respond to treatment [53]. In the last
instance [55], isolates from 2 patients who were unresponsive
to metronidazole were susceptible to metronidazole in vitro.
There is strong evidence that induced resistance to the nitroimidazoles in vitro is due to the inability of the parasite’s oxidoreductase to convert these compounds to their toxic metabolite [55–58]. To determine whether this holds true in vivo
would require sequence analysis of the enzyme in clinical isolates recovered from patients with infections that are refractory
to nitroimidazoles. Another report claims that the organisms
that had infected children and that were clinically resistant to
treatment with furazolidone had decreased susceptibility to the
drug in vitro [54].
It is important to assess the efficacy of treatments by use of
laboratory tests. We rely on the high sensitivity and specificity
of EIA assays for Giardia, which detect soluble Giardia cyst
wall proteins [59]. The results of this assay normally revert to
negative when patients are treated effectively. In all patients
who had been treated with quinacrine, the Giardia antigen was
no longer detected in stool samples by day 5 of treatment [60];
the duration of antigen persistence in the stool when other
drugs are used has not been defined, but it should be similar.
A persistently positive Giardia antigen test result that occurs
during a course of treatment suggests ineffective treatment. As
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Refractory Giardiasis • CID 2001:33 (1 July) • 27
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NOTE. Many 5 nitroimidazoles and some benzimidazoles have
in vivo efficacy in the treatment of Giardia infections. Most of the
aforementioned drugs, as well as those that are frequently used at
the present time, are excluded from the listing. There are no standard
assays for measuring in vitro susceptibility or in vivo efficacy in
animals. The in vitro susceptibility of drugs with accepted in vivo
efficacy in humans is not shown.
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