Antimicrobial Agents and Chemotherapy, May 1998, p. 1068-1072, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Drug Evaluation of Concurrent Pneumocystis
carinii, Toxoplasma gondii, and Mycobacterium
avium Complex Infections in a Rat Model
Monique
Brun-Pascaud,1,*
Premavathy
Rajagopalan-Levasseur,1
Françoise
Chau,1
Guylène
Bertrand,1
Louis
Garry,1
Francis
Derouin,2 and
Pierre-Marie
Girard3
Institut National de la Santé et de la
Recherche Médicale Unité 13 Hôpital Bichat-Claude
Bernard,1
Laboratoire de
Parasitologie-Mycologie, Hôpital
St-Louis,2 and
Service des Maladies
Infectieuses, Hôpital Rothschild,3 Paris,
France
Received 19 September 1997/Returned for modification 8 December
1997/Accepted 3 February 1998
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ABSTRACT |
We present a new experimental model for the simultaneous evaluation
of the activities of drugs against Pneumocystis
carinii, Toxoplasma gondii, and Mycobacterium
avium complex infections. Rats latently infected with
P. carinii were challenged with the MO-1 strain of
M. avium and then immunosuppressed with corticosteroids for
7 weeks. At week 5 the RH strain of T. gondii was
intraperitoneally injected. Organs were examined for the three
pathogens after death or killing of the animals at week 7. Without
treatment, rats challenged with T. gondii died
with pulmonary P. carinii infection and disseminated T. gondii and M. avium infections. In order to
assess the value of the model for evaluation of the activities of
drugs, we administered by oral gavage for 7 weeks drugs or combinations
of drugs selected for their individual efficacies against at least one
pathogen. We found that clarithromycin with sulfamethoxazole,
clarithromycin with atovaquone, roxithromycin with sulfamethoxazole or
dapsone, and rifabutin with atovaquone were effective against the three infections, whereas PS-15 with dapsone and trimethoprim with
sulfamethoxazole were active against Toxoplasma and
Pneumocystis infections only. This triple-infection rat
model offers a new tool for the simultaneous evaluation of the
activities of drugs against three of the major opportunistic infections
occurring in immunosuppressed individuals.
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INTRODUCTION |
Pneumocystis carinii,
Toxoplasma gondii, and disseminated Mycobacterium
avium complex infections are frequent opportunistic infections
that occur in AIDS patients. Drugs with activities against these
organisms are available, and the value of primary and secondary
prophylactic drug regimens has been demonstrated (38).
Current prophylactic strategies target both pneumocystosis and
toxoplasmosis, when required (25). Combined
prophylaxis for these two opportunistic infections has been
achieved with two-drug regimens, i.e.,
trimethoprim-sulfamethoxazole (12, 27) or
dapsone-pyrimethamine (20). The benefit of primary prophylaxis for M. avium complex infection with
rifabutin, clarithromycin, or azithromycin has been demonstrated
(29).
Despite these advances, evaluation of new curative and prophylactic
regimens for opportunistic infections is warranted to provide more
effective and/or better-tolerated strategies. Animal models are major
tools for this type of evaluation. Antipneumocystis drugs have mainly
been evaluated with latently infected rats (17, 24, 39) or
rats that are intratracheally inoculated (4) and then
immunosuppressed. Antitoxoplasma drugs are evaluated with healthy mice
(2, 15), and antimycobacterial agents are evaluated with
immunodeficient beige or C57BL/6 mice (18, 30). Individually, these models provide evidence of the activities of drugs,
but they are not well adapted in the setting of preventing multiple
opportunistic infections in the same host. Therefore, our goal was to
develop a rat model of multiple infections which takes into account the
potential interactions of the organisms in the development of each
infection and which permits the more rapid screening of drugs or
combinations of drugs with extended activity. The use of a single host
would also allow a simultaneous comparison of the respective efficacy
of each drug against different pathogens under similar pharmacokinetic
conditions.
With this goal in mind, we have extended the rat model of concurrent
infection with P. carinii and T. gondii
(11) to a model of infection with three
opportunistic pathogens by inducing active M. avium
complex infection along with active P. carinii and
T. gondii infections. After successfully establishing
infections with the three pathogens and examining whether there is an
interaction between them, we evaluated several drug combinations known
to be effective in single- or double-infection models.
(This work was presented in part at the 36th Interscience Conference on
Antimicrobial Agents and Chemotherapy, New Orleans, La., 15 to 18 September 1996 [7a].)
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MATERIALS AND METHODS |
Triple-infection model.
Male Wistar rats (weight, 180 to
200 g; Janvier Breeding Laboratories, Le Genest St. Isle, France)
were used.
This study was done in accordance with prevailing regulations regarding
the care and use of laboratory animals in the countries of the European
Community (Journal Officiel des Communautés Européennes, 18 December 1986, report L358). The experimental protocol is summarized in
Fig. 1.
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FIG. 1.
Schematic representation of the experimental protocol
for the triple-infection model. IV, bacteria were inoculated
intravenously; IP, tachyzoites of T. gondii were
inoculated intraperitoneally; #, rats were autopsied within 10 h
of death for determination of the pathogens.
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Induction of different infections.
P. carinii
infection was induced in latently infected rats by immunosuppression:
25 mg of cortisone acetate (Hydrocortisone; Hoechst-Roussel, Paris,
France) was injected subcutaneously twice weekly, and the rats were
given a low-protein (8%) diet (Usine Alimentation Rationelle,
Villemoisson, France).
M. avium complex strain MO-1, a clinical isolate from
an AIDS patient, was prepared as described previously (30).
At week zero rats were inoculated with 1.5 × 107
viable bacteria in a volume of 0.3 ml, which was injected intravenously into the jugular vein while the rats were under light ether anesthesia.
T. gondii infection was induced as described previously
(11). Briefly, after 5 weeks of corticosteroid
immunosuppression, the rats were inoculated intraperitoneally with
1.5 × 107 tachyzoites of the virulent RH strain of
T. gondii.
Assessment of different infections.
The different infections
were assessed as follows. The numbers of P. carinii
cysts in lung tissue were counted after enzymatic digestion and
toluidine blue O staining of the lung tissue, and the T. gondii organisms in lung, brain, liver, and spleen tissue specimens were titrated by a tissue culture method and an indirect immunofluorescence assay as described previously (11). For
M. avium, lung, spleen, and liver tissue specimens and
blood specimens were stored at 
80°C until they were processed. The
tissues were homogenized in 1 ml of sterile distilled water with a
glass homogenizer. Homogenates were decontaminated by a procedure which
has no effect on the yield of M. avium and which is
routinely used for the isolation of Mycobacterium
tuberculosis (21). Serial 10-fold dilutions of
homogenates were cultured on 7H11 agar plates supplemented with oleic
acid, albumin, dextrose, and catalase enrichment (Difco Laboratories,
Detroit, Mich.) (30). The colonies were counted after 14 days at 37°C, and the numbers of CFU per gram of tissue were
calculated.
Monitoring of development of infection in control rats.
After the evaluation of the basal level of P. carinii
infection in 8 rats, 45 rats were immunosuppressed to follow the
development of (i) a simple P. carinii infection after
5 and 7 weeks of immunosuppression (10 rats), (ii) a dual infection
with P. carinii and M. avium (20 rats),
(iii) a dual infection with P. carinii and
T. gondii (5 rats), and (iv) a triple infection with
P. carinii, T. gondii, and
M. avium (10 rats).
Evaluation of drug activity in the triple-infection model.
Forty rats were treated with combinations of drugs from the initiation
of the corticosteroid treatment to the end of the experiment. Each drug
was administered by the oral route 5 days a week for 5 weeks and then
every day after T. gondii inoculation until death or
killing of the animals after 7 weeks.
The choice of drug combinations was guided by their efficacies in the
treatment of P. carinii and T. gondii
in the rat model of dual infection as shown previously, as follows:
rifabutin at 100 mg/kg of body weight plus atovaquone at 100 mg/kg
(8), roxithromycin at 200 mg/kg plus sulfamethoxazole at 20 mg/kg or dapsone at 50 mg/kg (9), PS-15 at 25 mg/kg plus
dapsone at 25 mg/kg (10), and trimethoprim at 20 mg/kg plus
sulfamethoxazole at 100 mg/kg (11). In addition, the
synergistic activity of clarithromycin at 200 mg/kg plus a low dose of
sulfamethoxazole (20 mg/kg) or plus atovaquone at 100 mg/kg was also
examined because these combinations were shown to be active against
P. carinii in a rat model (1) and against
T. gondii in a mouse model (35). The goal
from the use of these drug combinations was to extend their activities
against M. avium infections: macrolides such as
clarithromycin are one of the most effective drugs against the
M. avium complex in humans (31, 36),
roxithromycin has been shown to have efficacy against the M. avium complex in vitro and in vivo (5, 33, 40), and
rifabutin has also been shown to have efficacy against M. avium complex infection in rat and mouse models (6,
26). Clarithromycin (Abbott Laboratories, North Chicago, Ill.),
sulfamethoxazole (Sigma, Paris, France), roxithromycin (Roussel Uclaf,
Romainville, France), dapsone (Rhône-Poulenc-Rorer, Antony,
France), rifabutin (Pharmacia Upjohn Laboratories, Milan, Italy), and
PS-15 (Jacobus Pharmaceutical Co. Inc., Princeton, N.J.), all of which
were in the powder form, were prepared in 1% carboxymethyl cellulose
in sterile 0.9% saline solution and were briefly sonicated. Atovaquone
(Wellcome Foundation, Beckenham, United Kingdom) was used in the
suspension form, and trimethoprim combined with sulfamethoxazole
(Roche, Neuilly-sur-Seine, France) was used in the pediatric solution
form.
Statistical analysis.
P. carinii cyst counts,
T. gondii burdens, and the numbers of M. avium CFU (per gram of tissue) were expressed as the mean log
value ± 1 standard deviation. Results were analyzed by one-way analysis of variance, and each pair of groups of interest was compared
by Bonferroni's adjusted t test.
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RESULTS |
Monitoring of P. carinii, T. gondii, and M. avium infections in control rats.
(i) Development of P. carinii in single, dual, and
triple infections.
The time course of P. carinii
development as a single infection is presented in Table
1. The baseline value was log 3.3 ± 0.6 cysts/g of lung, reflecting the latent infection. After 5 and 7 weeks of immunosuppression, the levels reached log 6.3 ± 0.8 and
log 7.2 ± 0.3 cysts/g, respectively (P < 0.01).
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TABLE 1.
P. carinii infection as a single
infection, as a dual infection with T. gondii or
M. avium, and as a triple infection with
T. gondii and M. avium
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After 5 and 7 weeks of immunosuppression, the levels of P. carinii cysts in rats inoculated with M. avium
complex reached log 6.1 ± 0.5 and log 7.2 ± 0.2 cysts/g,
respectively (P < 0.01). After 5 weeks of
immunosuppression the P. carinii cyst number was log
6.2 ± 0.5/g in rats infected with T. gondii. When
rats were infected with T. gondii and M. avium, the P. carinii cyst number was log 6.4 ± 0.6/g. When these values were compared at the same time of
immunosuppression, there was no difference between these values.
Therefore, the P. carinii infection was not modified by
the infection with the two other pathogens.
(ii) Development of T. gondii in dual and triple
infections.
Rats latently infected with P. carinii
and inoculated with T. gondii after 5 weeks of
immunosuppression died by 6.2 ± 1.8 days postinoculation; pleural
fluid was found, and all examined organs exhibited T. gondii infection (Table 2). Of the
10 rats latently infected with P. carinii, inoculated
with M. avium complex, and then challenged with
T. gondii at week 5, 9 died by 5.7 ± 0.2 days.
The mean number of days to death, pleural fluid volumes, and
T. gondii burdens in the organs were similar to those
obtained for rats infected with P. carinii and
T. gondii. Therefore, T. gondii
infection was not modified by M. avium infection.
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TABLE 2.
Characteristics of T. gondii infection in
immunosuppressed rats as a dual infection with P. carinii and as a triple infection with P. carinii and M. avium
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(iii) Development of M. avium in dual and triple
infections.
Rats latently infected with P. carinii, inoculated with M. avium, and killed
after 5 and 7 weeks of immunosuppression showed similar levels of
disseminated M. avium complex infection in their lungs,
spleens, livers, and blood (Table 3).
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TABLE 3.
Characteristics of M. avium complex
infection in immunosuppressed rats as a dual infection with
P. carinii and as a triple infection with
P. carinii and T. gondii
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Rats inoculated with the third pathogen (T. gondii)
died 5.7 ± 0.2 days after inoculation; bacteria were found in the
pleural fluid, and the levels of M. avium complex
infection in their organs were similar to those observed in rats with
dual P. carinii and M. avium
infections. Therefore, M. avium infection in rats
infected with P. carinii was not modified by
T. gondii infection.
Evaluation of drug activity in the triple-infection model.
The
results of the evaluation of drug activity are indicated in Table
4 for P. carinii and
T. gondii infections and in Fig. 2A to D for M. avium
complex infection. Untreated rats died 5.7 ± 0.2 days after
inoculation of T. gondii; 3.4 ± 1.8 ml of pleural fluid was found. T. gondii burdens were found in the
pleural fluid, lungs, brains, spleens, and livers, P. carinii cysts were found in the lungs, and M. avium was found in the pleural fluid, lungs, spleens, livers, and
blood. Thirty-eight treated rats survived and were killed after 7 weeks
of treatment. Two rats died during the course of treatment: one in the
rifabutin-atovaquone group (shortly after gavage) and the other in the
PS-15-dapsone group (from a nonmycobacterial infection). The results
indicate that (i) P. carinii infection was fully
prevented in all treated rats, whereas it was not prevented in
untreated control rats; (ii) T. gondii was found only
in the spleen of one rat treated with the PS-15-dapsone combination;
and (iii) compared to the levels of M. avium
complex organisms obtained in untreated rats, the CFU counts
after the administration of either
clarithromycin-sulfamethoxazole, clarithromycin-atovaquone,
rifabutin-atovaquone, roxithromycin-dapsone, or
roxithromycin-sulfamethoxazole combinations were significantly decreased in the lungs, spleen, and liver (P < 0.01)
(Fig. 2A, B, and C) and no bacteremia was detected (limit of detection, 10 CFU/mL) (Fig. 2D). The combinations PS-15-dapsone and
trimethoprim-sulfamethoxazole were not found to be
efficacious against M. avium complex infection, although a slight decrease in CFU counts in blood was observed.
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TABLE 4.
Activities of different drug regimens on P. carinii and T. gondii burdens in tissues in the
rat model of concurrent pneumocystosis, toxoplasmosis, and
M. avium complex infection
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FIG. 2.
Activities of different drug regimens on M. avium levels in lungs (A), spleens (B), livers (C), and blood (D)
in the rat model of concurrent pneumocystosis, toxoplasmosis, and
M. avium infection. *, P < 0.01 versus untreated controls. (a), value for one rat. See footnote
a of Table 4 for definitions of abbreviations.
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DISCUSSION |
In the setting of human immunodeficiency virus (HIV)
infection, improved strategies for prophylaxis for the most
frequent and severe opportunistic infections need to be
developed. Although the advances in antiretroviral therapy have
markedly decreased the level of progression of immune system
deterioration and have improved the survival of patients with HIV
infection, large numbers of HIV-infected patients remain at risk for
the development of opportunistic infections. New challenges have
emerged. While prophylaxis for pneumocystosis is well established,
opportunistic infections associated with more severe immunosuppression
such as localized cytomegalovirus infections or disseminated
M. avium complex infection continue to occur
(22). This phenomenon justifies the need to extend the
spectra of prophylactic regimens by taking into account the activities
of compounds alone or in combination against several pathogens. In
addition, the introduction of anti-HIV protease inhibitors which
strongly interact with cytochrome P-450 have raised new pharmacological
difficulties from the use of multiple drugs against opportunistic
pathogens. Thus, we extended the model of a double infection
(11) to a model of a triple infection that includes
M. avium complex infection because of the frequency of
occurrence of such infections in immunosuppressed patients and the
susceptibility of M. avium to the drugs already used
against T. gondii.
In the present model, active infections with P. carinii, T. gondii, and M. avium
were obtained. The levels of P. carinii burdens in the
lungs were similar to those evaluated in the lungs of
corticosteroid-treated rats, which is a model routinely used by
numerous investigators (23) and which has been proved to be
highly useful in predicting the efficacies of drugs in humans (24,
39). T. gondii infection in multiple organs was
successfully achieved after inoculation of rats with the virulent RH
strain, and parasite burdens were not different from those obtained in
mouse models previously used to screen the activities of drugs against
T. gondii (32). Although this model of
subacute disseminated infection differs from the infection reactivation
observed in immunosuppressed patients, it is nonetheless predictive of
the clinical activities of anti-T. gondii drugs
(11). In addition to T. gondii counts, the
efficacies of drugs can be assessed by comparing the survival rates
since toxoplasma infections are lethal. We also found that
M. avium complex infection could be established in
several organs and blood, although the level of infection was slightly
lower than that in immunodeficient mouse models (19).
The rationale for testing several combinations of drugs with potential
activity against at least one pathogen was to validate this new model
for the evaluation of the activities of drugs. The results confirm that
several drug combinations are interesting candidates against the three
infections and suggest the ability of this model to predict drug
activity because the results are consistent with those obtained
with classical one-pathogen models. The combination of a macrolide
(clarithromycin or roxithromycin) with a sulfonamide or dapsone reduced
the burdens of the three microorganisms and prevented mortality.
The eradication of M. avium complex infection from
tissues was not achieved, although bacteremia was abolished, which is
consistent with observations with other animal models and for humans
(6, 7, 13, 18, 26, 30). Clarithromycin plus atovaquone or
rifabutin plus atovaquone was as effective as the previous combinations
and could avoid the frequent undesirable sulfonamide- or
dapsone-related side effects which are particularly common in
HIV-infected patients (38). The anti-P.
carinii and anti-T. gondii activities of the rifabutin-atovaquone combination are consistent with those described in
recent studies demonstrating that the combination has synergistic activity against P. carinii (14) and
T. gondii (3, 34). In contrast,
trimethoprim-sulfamethoxazole was not efficacious against M. avium complex infection in our study, and the results of our study
do not support the clinical efficacy of that combination suggested by
one group (16). PS-15 plus dapsone appeared to be effective
only against P. carinii and T. gondii
infections, confirming previous observations (10). No
significant activity against the M. avium complex was
observed, which is in contrast to the observations made in vitro by
other teams (28, 37).
The extrapolation of the data regarding the activities of the drug
combinations to their clinical use in HIV-infected patients should be
done with caution. It must be kept in mind that the mechanism of
immunosuppression induced by corticosteroids is far different from the
mechanism of HIV-related immunodeficiency and that the means of
acquisition of each opportunistic infection in animals with
corticosteroid-induced immunosuppression differ from those in
patients with AIDS. Nevertheless, previous murine models of
single opportunistic infections based on a similar experimental approach have been shown to be reliable for the preclinical evaluation of drug efficacy.
In conclusion, a rat model of triple infection with P. carinii, T. gondii, and M. avium
has been designed and has been used to demonstrate the efficacies of
several drug combinations. Compared to separate models of single
infections, which often use different animal species, this model offers
the opportunity to evaluate simultaneously the activities of drugs
against different pathogens. The use of a single immunocompromised host
is an advantage for the more rapid identification of candidate drug
regimens with activity against opportunistic pathogens and for the
evaluation of the activities of drugs under similar pharmacokinetic
conditions.
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ACKNOWLEDGMENTS |
This study was supported in part by a grant from the Agence
Nationale pour la Recherche sur le SIDA and by SIDACTION.
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FOOTNOTES |
*
Corresponding author. Mailing address: INSERM U 13, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris
Cedex 18, France. Phone: 33 1 40 25 86 05. Fax: 33 1 40 25 86 02. E-mail: u13bcb{at}magic.fr.
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Antimicrobial Agents and Chemotherapy, May 1998, p. 1068-1072, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
