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J Clin Pathol: first published as 10.1136/jcp.51.2.138 on 1 February 1998. Downloaded from http://jcp.bmj.com/ on 15 January 2019 by guest. Protected by copyright.
stable remission and possible eradication after
long term, low dose azithromycin
D Dionisio, A Orsi, G Sterrantino, M Meli, S Di Lollo, L Ibba Manneschi, M Trotta,
M Pozzi, L Sani, F Leoncini
rats, although eradication was not achieved sis, electrolytes, liver function tests, and
with the schedules of treatment used in these abdominal ultrasonography.
J Clin Pathol: first published as 10.1136/jcp.51.2.138 on 1 February 1998. Downloaded from http://jcp.bmj.com/ on 15 January 2019 by guest. Protected by copyright.
experiments.9 12 Azithromycin was administered orally to all
In man, the results of azithromycin treat- patients who were divided into three groups:
ment for cryptosporidiosis are conflicting; group A received 500 mg daily (6 patients),
however, there have been reported successes in group B received 1000 mg daily (3 patients),
immunocompromised children and suggestion and group C received 1500 mg daily (4
of clinical and parasitological responses in patients) (table 1). Assignment to each group
AIDS patients after short term treatment, and length of treatment were based on patient
especially with high doses.1–3 5 13–16 compliance and concurrent treatments for
To our knowledge, no long term azithro- coexisting diseases. Four of the 13 patients did
mycin treatment for AIDS related crypto- not continue into maintenance treatment
sporidiosis has been reported in the literature, because of the severity of coexisting diseases
although data from animal models suggest that (cases 4, 5, and 9) or the probable eradication
long term continuous administration may be after initial treatment (case 7). The remaining
necessary in the immunocompromised host.12 9 patients (4 from group A, 1 from group B,
We provided long term, low dose azithromycin and all 4 patients from group C) continued
treatment for chronic cryptosporidiosis in azithromycin into maintenance treatment with
immunodeficient patients with AIDS, and our diVerent schedules of treatment for 30 to 360
results suggest that this regimen may induce days (mean 129) (table 2). Again, assignment
stable remission of the infection, and may lead to each schedule was based on patient compli-
to eradication in some cases. ance and concurrent treatments for coexisting
diseases. Three patients who had chosen to
stop treatment after the initial course (cases 8,
Patients and methods 11, and 12), began maintenance treatment
Thirteen HIV infected patients (11 male, 2 after relapse.
female) with chronic cryptosporidiosis were Written informed consent was obtained
studied. All but one patient had previously had before treatment. No concomitant antidiar-
standard courses with paromomycin4 leading rhoeal drugs were administered. Clinical as-
to only transient symptomatic relief, with sessment, and haematological and liver func-
relapse occurring a few days after the treatment tion tests were monitored at 10 day intervals
was discontinued. The patients were aged during treatment. At the end of treatment,
between 30 and 47 years (mean 35.6). Nine CD4+ T cell count was repeated in patients
patients were homosexual and four were drug who had received treatment for longer than
addicts. CD4+ T cell count ranged from three months.19 Adverse events were evaluated.
0–85 × 106/l in 12 patients (mean 24.3); it was Response to treatment was monitored by the
162 × 106/l in the other patient. All 13 patients search for oocysts in stool (one sample each
had AIDS at the time of study entry; AIDS day for three days) twice monthly during treat-
defining events were cryptosporidiosis in eight ment and monthly after treatment, and by
cases, and oesophageal candidiasis, cytomega- charting daily stool frequency and body weight.
lovirus infection, pneumocystosis, systemic A complete response was defined as cessa-
Mycobacterium avium infection, and Kaposi’s tion of diarrhoea (stool frequency less than
sarcoma in the other five cases, respectively. All three times each day), stabilisation of body
patients had chronic diarrhoea (at least two weight, and significant decrease or clearance of
months) with a range of 3–10 watery stools oocyst shedding in stool lasting less than one
each day (mean 6). Weight loss ranged from year. A partial response was defined as more
5–17 kg (mean 9). than 50% reduction in baseline stool fre-
Stools were processed by modified acid-fast quency, with continuing weight loss, and either
staining to detect cryptosporidia.17 The slight or no decrease of oocyst shedding in
amount of oocyst shedding was evaluated by a stool. No response was defined as no improve-
semiquantitative method on 100 microscopic ment in either clinical or parasitological
fields: oocysts were defined as very frequent if baseline parameters. Probable eradication was
present in every field, frequent if present in defined as normal bowel movements with
more than 50 but fewer than 100 fields, rare if formed stool, stabilisation of body weight to
present in fewer than 50 fields, and very rare if preinfection level, and oocyst clearance in stool
sporadically present. Before study entry, fre- lasting at least one year.
quent to very frequent oocysts of cryptosporid-
ium were present in all patients’ stool.18 All Results
patients had diagnosis confirmed by light and INITIAL TREATMENT
transmission electron microscopy of endo- A complete response was observed in 10
scopic biopsy specimens taken from the third patients (5 from group A, 2 from group B, and
tract of the duodenum. Stool samples were also 3 from group C) (table 1). The remaining three
examined for bacteria, Clostridium diYcile patients showed partial response, no response,
toxin, mycobacteria, mycetes, adenoviruses and probable eradication, respectively (table
and rotaviruses, microsporidia, and other para- 1).
sites, with positive results in two patients who In the 10 patients who responded com-
had Aeromonas hydrophila and Giardia lamblia, pletely, a clinical response was obtained 1–30
respectively. days from starting treatment (mean 6.8), while
All patients underwent a baseline evaluation a parasitological response (very rare faecal
that included full blood cell count, urine analy- oocysts) was observed from 14–30 days (mean
140 Dionisio, Orsi, Sterrantino, et al
18.4). Case 1 also showed relief from coexist- daily stools decreased from 8 to 3 from the sec-
ing acalcolous cholecystitis (unresponsive to ond day of treatment, and faecal oocysts
J Clin Pathol: first published as 10.1136/jcp.51.2.138 on 1 February 1998. Downloaded from http://jcp.bmj.com/ on 15 January 2019 by guest. Protected by copyright.
previous paromomycin courses) from the third decreased from very frequent to frequent three
day of treatment, supporting a probable crypto- weeks after starting treatment.
sporidial aetiology. No diVerences in the time There was no apparent response in a patient
to a complete response, either clinical or para- receiving 1500 mg daily for 20 days (case 10).
sitological, were documented among the three In this case, the parasite load in stool did not
study groups. decrease, and side eVects, such as worsening of
Probable eradication was achieved by a 21
diarrhoea (up to 15 watery stools each day) and
day course of 1000 mg azithromycin daily in
abdominal cramps, were observed during
the patient with a CD4+ T cell count of
162 × 106/l (case 7). In this case, diarrhoea treatment. These side eVects, however,
ceased a week after starting treatment, and promptly reversed by restarting azithromycin
oocyst clearance in stool, with gain in body at a lower daily dose (table 2). The same side
weight, was evident from the end of treatment. eVects, although less pronounced, were tran-
Neither clinical nor parasitological relapse was siently present in two other patients also
documented until the patient’s death one year receiving azithromycin 1500 mg daily (cases 12
later from tuberculosis. and 13). No adverse reactions were docu-
A partial response was observed in a patient mented in patients receiving lower daily doses
receiving 500 mg daily for 40 days (case 4): of azithromycin.
Table 1 Results of initial treatment with azithromycin
Length of
CD4 count treatment
Case (×106/l) (days) Response Follow up Maintenance Cause of death
CR, complete response; PR, partial response; PER, probable eradication; NR, no response.
Length of
treatment
Case Dose (days) Response Follow up Cause of death
Table 3 Coexisting diseases from stool 30 and 120 days from starting
maintenance treatment, respectively. Both pa-
J Clin Pathol: first published as 10.1136/jcp.51.2.138 on 1 February 1998. Downloaded from http://jcp.bmj.com/ on 15 January 2019 by guest. Protected by copyright.
Case Disease Treatment
tients recovered their preinfection weight and
1 Kaposi’s sarcoma (systemic) None remained asymptomatic with no oocysts in
Cytomegalovirus infection (systemic) Ganciclovir stool, 21 and 14 months after completion of
Toxoplasmosis (CNS) Cotrimoxazole
Staphylococcus epidermidis infection (sepsis) Vancomycin treatment, respectively (table 2).
Giardiasis (intestine) Albendazole During the whole course of azithromycin,
2 Candidiasis (mouth, oesophagus) Fluconazole several coexisting diseases developed in each
Mycobacterium xenopi infection (lung) None
3 Candidiasis (mouth) Fluconazole patient (table 3), and no improvement in
Mycobacterium avium infection (systemic) Rifabutin, clofazimine, ethambutol CD4+ T cell count was documented.
4 Candidiasis (oesophagus) Fluconazole
Kaposi’s sarcoma (systemic) None
5 Candidiasis (oesophagus) Fluconazole Discussion
Kaposi’s sarcoma (systemic) None Azithromycin has been tested in clinical trials
Cytomegalovirus infection (eye, rectum) Ganciclovir, foscarnet
6 Candidiasis (oesophagus) Fluconazole
for cryptosporidiosis in immunocompromised
Cytomegalovirus infection (eye) Ganciclovir, foscarnet patients; however, in all these studies the drug
Aeromonas hydrophila infection (intestine) Ciprofloxacin was used for short term treatment.1–3 5 13–16 To
7 Tuberculosis (lung) Isoniazide, rifampin, ethambutol,
streptomycin our knowledge, this is the first trial showing
8 Candidiasis (mouth) Fluconazole results after long term treatment.
Kaposi’s sarcoma (systemic) None Long term, low dose azithromycin treatment
9 Candidiasis (oesophagus) Fluconazole
Progressive multifocal leukoencephalopathy None was associated with pronounced clinical and
(CNS) parasitological benefit in nine severely immu-
10 Candidiasis (oesophagus) Fluconazole nodeficient patients with AIDS: two patients
11 Candidiasis (oesophagus) Fluconazole
Cytomegalovirus infection (eye) Ganciclovir probably had the infection eradicated, and
12 Citrobacter freundii abscess (perianal) Surgical drainage, ciprofloxacin seven patients showed a persistent complete
13 Candidiasis (oesophagus) Fluconazole response with high decrease (five patients) or
Kaposi’s sarcoma (systemic) None
clearance (two patients) of parasite in stool.
The drug was well tolerated, and there was no
Three patients (cases 8, 11, and 12) relapsed relapse, either during treatment or many
21, 28, and 49 days after treatment was discon- months after treatment.
tinued, respectively, while two others (cases 5, These results are more impressive than those
and 9) showed no relapse until death 30 and 90 we observed after short term initial azithromy-
days after completion of treatment, respectively cin. The initial course, although associated
(table 1). with both clinical and parasitological benefit,
was unable to achieve parasite clearance in
MAINTENANCE TREATMENT stool (except in one patient with less advanced
Nine of the 13 patients continued into long immunodeficiency), or to prevent relapse in the
term maintenance treatment with four sched- three patients who discontinued treatment.
ules of treatment (table 2): azithromycin was Azithromycin at high doses did not give better
administered at 500 mg 3 days each week to 3 results than at low doses, and reversible side
patients from group A (cases 1, 2, and 3), and eVects occurred with the 1500 mg daily dose.
to 1 patient from group B (case 8); at 500 mg Our results are in agreement with those
daily to 1 patient from group A (case 6), and to obtained in animal models of cryptosporidiosis
2 patients from group C (cases 10, and 13); at that emphasise the need for long term continu-
500 mg daily for 30 days, followed by 500 mg 5 ous administration of azithromycin in immu-
days each week, to 1 patient from group C nocompromised hosts.12 Our results suggest
(case 11); and at 500 mg daily for 30 days, fol- that low dose long term azithromycin treat-
lowed by 500 mg 3 days each week to another ment would be adequate to avoid relapse and,
patient from group C (case 12). All schedules possibly, to achieve eradication of chronic
of treatment were well tolerated. cryptosporidiosis in some patients with ex-
Complete response was observed in 7 tremely low CD4+ T cell counts. Our data
patients and probable eradication in 2 patients indicate that low dose, long term azithromycin
(table 2). can give better results than standard paromo-
Cases 1, 2, 3, 6, and 13 had a persistent mycin, which is known to allow relapses either
complete response, with no relapse until death during or shortly after stopping treatment.1–3
(table 2). Furthermore, case 13 also showed The regimen we used required long term
clearance of parasite in stool lasting until death. treatment, but azithromycin was well tolerated,
No symptomatic reactivation of acalcolous adverse reactions occurred only with the high-
cholecystitis was documented in case 1 until est dose (1500 mg daily), and promptly
death. reversed when a lower dose was started. These
Case 8, who received maintenance treatment data are in agreement with the literature,
for one year, was still free from symptoms, and showing good tolerance of azithromycin in
with a low parasite load in stool, eight months man,10 and support its safety for chronic use.
after interruption of treatment (table 2). The eVects on cryptosporidiosis were obtained
Case 11 achieved parasite clearance five despite the fact that several opportunistic
months from starting maintenance treatment, infections developed during the course of
and was still free from symptoms, with no treatment, and no improvement in CD4+ T
oocysts in stool, six months after interruption cell count was documented.
of treatment (table 2). In spite of its small size, this study supports
The infection was probably eradicated in the eVectiveness and safety of azithromycin for
cases 10 and 12; there was parasite clearance treating chronic cryptosporidiosis in patients
142 Dionisio, Orsi, Sterrantino, et al
with AIDS, and highlights the importance of 2 Adal KA. From Wisconsin to Nepal: cryptosporidium,
cyclospora, and microsporidia. Curr Opin Infect Dis 1994;7:
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