No effective drug and definitive “gold standard” treatment for Toxoplasma gondii (T. gondii) infection has been available so far, though some medicines have been commonly used in the treatment of T. gondii infection, such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C). A systematic review and meta-analysis were performed to compare the efficacies of these conventional medicines in the treatment. Cohort studies for the treatment of acute T. gondii infection were searched from PubMed, Google Scholar, ect. All the cases number for different group extracted from each included literature were input to meta-analysis 3.13 software to calculate the pooled negative conversion rate (NCR), cure rate (CR) or vertical transmission rate based on their sample size and weight. The pooled NCR with 95% confidence intervals (CI) was used to evaluate the overall rate of a diagnosis positive result conversion to a negative result after treatment, which of spiramycin, azithromycin and TCM were 83.4% (95%CI, 72.1%-90.8%), 82.5% (95%CI, 75.9%-87.6%), and 85.5% (95%CI, 71.3%-93.3%) respectively, with no statistical difference between them. The pooled CR with 95% CI was used to evaluate the overall rate of complete disappearance of clinical symptoms for toxoplasmic encephalitis after therapy, which of P-S, TMP-SMX, and P-C were 49.8% (95%CI, 38. 8% -60.8%), 59.9% (95%CI, 48.9%-70.0%), and 47.6% (95%CI, 24.8%-71.4%) respectively, with no statistical difference between them. Primary T. gondii infection in pregnancy was treated mainly with spiramycin alone or combined with other drugs, and the pooled rate of vertical transmission was about 9.9% (95%CI, 5.9%-16.2%) after therapy. Toxoplasmic encephalitis in AIDS patients was usually treated with sulfonamides combined with other drugs and the pooled CR was 49.4% (95%CI, 37.9%-60.9%).
Citation: Wei H-X, Wei S-S, Lindsay DS, Peng H-J (2015) A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans. PLoS ONE 10(9): e0138204. https://doi.org/10.1371/journal.pone.0138204
Editor: Gordon Langsley, Institut national de la santé et de la recherche médicale - Institut Cochin, FRANCE
Received: January 6, 2015; Accepted: July 20, 2015; Published: September 22, 2015
Copyright: © 2015 Wei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: Supported by the funding of National Natural Science Foundation of China (No. 81572012, 81271866), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2014).
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: P-S, pyrimethamine and sulfadiazine combination; P-C, pyrimethamine and clindamycin combination; TMP-SMX, trimethoprim and sulfamethoxazole combination; TCM, traditional Chinese medicine; NCR, negative conversion rates; CI, confidence interval; CR, cure rate
It is estimated that 1/3 of the world's population is infected with Toxoplasma gondii . The infection is asymptomatic in most immunocompetent people, but serious consequences and even death may occur in immunocompromised patients. Foetal death, malformation or abortion may occur in pregnant women who have no previous exposure or immunity to T. gondii [2, 3]. Agents used to treat toxoplasmosis act against the replicating tachyzoite stage, which is metabolically active as it destroys tissues and disseminates throughout the patients’ bodies. Once a chronic infection of T. gondii becomes established, the tachyzoites produce latent tissue cyst stages. The tissue cyst stages contain bradyzoites, which are only minimally metabolically active. Most drugs used to treat T. gondii do not significantly affect the tissue cyst stage or the bradyzoites. The tissue cysts produced in the brain are protected by the blood-brain barrier, which makes treatment even more difficult. Furthermore, if the patients become immune suppressed, the tissue cysts may rupture, and the bradyzoites will transform back to rapidly multiplying tachyzoites, leading to a focal or diffuse encephalitis [4, 5].The most common used therapeutic medicines for T. gondii infection are pyrimethamine and sulfadiazine. For patients with hypersensitivity to sulfonamides, pyrimethamine alone in high dosages or in combination with clindamycin, clarithromycin, azithromycin or atovaquone can be used as substitutes [6, 7]. Other medicines, including spiramycin, azithromycin, trimethoprim plus sulfamethoxazole (TMP-SMX), are also commonly used. Traditional Chinese medicine (TCM) formulae containing herbs Astragalus membranaceus, Scutellaria baicalensis, Artemisia annua, Ginkgo biloba etc are also used in the treatment of T. gondii infections [8–10]. Spiramycin has minimal foetal toxicity and can be effectively absorbed after oral administration, spreading quickly to tissues to kill the tachyzoites and reduce the parasite or prevent the parasite from spreading through the placenta to the foetus . Several studies revealed that maternal treatment with spiramycin alone or in combination with cotrimoxazole reduced the possibility of T. gondii vertical transmission and the disease sequelae in newborns, and delayed fetal infection [12–14], while it was also mentioned that the evidence was weak for early treatment in maternal infection reducing the risk of vertical transmission . In the treatment of toxoplasmic encephalitis, pyrimethamine- sulfadiazine (P-S), which is often the first line of treatment, results in clinical or radiographic improvement in 70% to 90% of patients [7, 16]. Reports on the treatment of toxoplasmic encephalitis in AIDS patients also indicate that the efficacy of P-S, and pyrimethamine plus clindamycin (P-C) are not significantly different in the acute phase treatment, but in the maintenance phase of that treatment, relapse rate was twice as high among patients in the P-C treatment group . A systematic review and meta-analysis on the treatment and control of toxoplasmic retinochoroiditis has been published, and there is a lack of evidence to support routine antibiotic treatment being effective for acute Toxoplasma retinochoroiditis [18, 19].
To resolve the uncertainty regarding the treatment efficacy of these drugs, we conducted a systematic review of the literature and a meta-analysis to explore the therapeutic effects of different drugs used in the treatment of T. gondii infection. Because different groups of people may need different therapeutic drugs, the treatments of T. gondii infection in pregnant women and toxoplasmic encephalitis patients were specifically analyzed here.
2.1 Search strategy
Our study was performed according to the recommendations of the PRISMA Statement  (see S1 Checklist). PubMed, Google Scholar, Cochrane Library, Medline, Wanfang database, CNKI, and Chinese medical Citation Database, were searched combining the terms "Toxoplasma gondii infection" or "toxoplasmosis" and "treatment" or "therapy" or "cure" or "drug therapy".
2.2 Inclusion and exclusion criteria
Studies were included if they meet the criteria as follows: (i) it was a cohort study; (ii) clinical trials were based on humans, rather than animals; (iii) when more than one article was based on a study of the same population, the one with the highest quality (the Science Citation Index (SCI) was highest or the citations of the article were highest) was chosen; (iv) the diagnosis of T. gondii infection was based on a serological examination for T. gondii antibodies (IgA, IgG and /or IgM), parasite observation, or PCR detection of DNA; a positive result was represented by the presence of IgM, IgA, significant increase in specific IgG or a positive parasite observation, and a positive PCR result in detection of T. gondii DNA; a negative result was defined as a lack of IgM, IgA, a significantly dropped or absent titer of IgG, a negative PCR result when detecting T. gondii DNA, or a negative parasite observation. (v) for toxoplasmosis cure rate evaluation, only toxoplasmic encephalitis was included, T. gondii infection diagnosis refer to (iv), encephalitis was confirmed by computed tomography or magnetic resonance imaging scans, and clinical signs or symptoms included fever, headache, seizures, lethargy-coma, hemiplegia or hemiparesis and so on; (vi) the diagnosis of congenital T. gondii infection met one of the following standards: A. increase of specific IgG in the first 12 months of age or persistence of specific IgG antibodies beyond 7 months till 12 months of age; B. positive with T. gondii specific IgM and/or IgA in cord blood and/or in neonatal blood; C. presence of parasite in amniotic fluid, placenta or fetal blood confirmed by inoculation to mice ascites, or by PCR test. The vertical transmission rate represents the risk of congenital infection when a mother was infected by T. gondii.
All the cases number for different group extracted from each included literature were input to meta-analysis 3.13 software to calculate the pooled negative conversion rate (NCR) or cure rate (CR) or vertical transmission rate based on their sample size and weight. NCR is valuable in the assessment of the treatment effects in asymptomatic infections, and CR is intuitionistic in the evaluation of symptomatic infections. The pooled NCR shows the overall rate of a positive diagnosis conversion to a negative diagnosis of T. gondii antibody or DNA, with a treatment time of generally less than a month. The pooled CR of toxoplasmic encephalitis is defined as "the overall rate of complete absence of clinical symptoms of encephalitis after therapy".
Citations were excluded for the following reasons:(i) the paper was a review or a descriptive study; (ii) the data were duplicated from other studies or we were unable to obtain.
2.3 Data extraction
The following information was extracted from each study: first author, publication time, the sample size, diagnostic methods, drug and drug dosage. The data were collected independently by two investigators (H-X. W & S-S. W). When the literature citations were controversial, these investigators discussed them and reached a consensus on inclusion or exclusion.
2.4 Data analysis
As spiramycin, azithromycin and traditional Chinese medicine (TCM) were commonly used in the treatment of general population or pregnant women infection with T. gondii which were usually asymptomatic, their therapeutic efficacies were evaluated with negative conversion rate (NCR) after treatment. As pyrimethamine-sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C) were commonly used in the treatment of toxoplasmic encephalitis, their therapeutic efficacies as well as the effects of the treatments in AIDS patients with toxoplasmic encephalitis were evaluated with cure rate (CR). The risk of T. gondii vertical transmission after the treatment of primary infection in pregnant women was evaluated with the overall vertical transmission rate after maternal treatment. In this meta-analysis, the heterogeneity among the studies was tested by a χ2-based Q test or I2 statistic . When p<0.05 or I2>50%, the heterogeneity was considered significant. A random-effects model was chosen to calculate the pooled NCRs or CRs or vertical transmission rate when the heterogeneity was significant, otherwise a fixed-effects model was used. Meta-analysis 3.13 software (Tufts Medical Centre, Boston, MA, USA) was used in this research. The therapeutic effects were compared with SPSS 13.0 software (Chicago, USA) between any two different drugs. The variance homogeneity of the extracted data was measured first. Analysis of variance (ANOVA) was conducted if it met the homogeneity of variance; otherwise, the rank sum test was used.
3.1 Analysis of the included literature
Forty-one publications matched the inclusion criteria, including 9 studies about the treatment with spiramycin [1–9 in S1 Appendix], 4 with azithromycin [8, 10–12 in S1 Appendix], 7 with TCM [5, 12–17 in S1 Appendix], 7 with pyrimethamine-sulfadiazine (P-S) [18–24 in S1 Appendix], 3 with trimethoprim-sulfamethoxazole (TMP-SMX) [18, 24, 25 in S1 Appendix], 6 with pyrimethamine-clindamycin (P-C) [19, 20, 26–29 in S1 Appendix], 11 concerning the risk of vertical transmission from the pregnant women in primary infection of T. gondii after treatment [6, 30–39 in S1 Appendix] and 14 about the treatment of toxoplasmic encephalitis in AIDS patients [18–29, 38, 39 in S1 Appendix]. Details about the first author, publication time, sample size, diagnostic methods and drug dosage are shown in Tables 1–8 in S1 Appendix. A flow diagram of the selection and nature of the studies is shown in Fig 1.
3.2 Quantitative synthesis and heterogeneity analysis
3.2.1 The pooled negative conversion rate (NCR) of spiramycin, azithromycin and TCM treatment for Toxoplasma gondii infection.
For spiramycin treatment, 9 publications with 315 participants were included (Table A in S1 Appendix); the NCR (95%CI) was 84.3% (71.9%-91.8%), calculated with the random-effects model (p = 0.000, I2 = 43.4%). For azithromycin treatment, 4 publications with 181 participants were included (Table B in S1 Appendix); the NCR (95%CI) was 82.5% (75.9%-87.6%), calculated with the fixed-effects model (p = 0.090, I2 = 34.3%). For TCM, 7 publications with 395 participants were included (Table C in S1 Appendix); the NCR (95%CI) was 85.5% (71.3%-93.3%), calculated with the random-effects model (p = 0.000, I2 = 46.6%). No statistically significant difference was found in the therapeutic effects of spiramycin, azithromycin, or TCM (p = 0.915 in the one-way ANOVA test for 3 independent-samples; p = 0.658 in the test of homogeneity of variances). All the details about the therapeutic effects in NCR of these medicines were shown in Fig 2.
3.2.2 The pooled cure rate (CR) of P-S, TMP-SMX and P-C in toxoplasmic encephalitis treatment.
For P-S treatment, 7 publications with 414 participants were included (Table D in S1 Appendix); the CR was 49.8% (95%CI, 38.8%-60.8%), calculated with the random-effects model (p = 0.000, I2 = 43.1%). For TMP-SMX treatment, 3 publications with 86 participants were included (Table E in S1 Appendix); the CR was 59.9% (95%CI, 48.9%-70.0%) calculated with the fixed-effects model (p = 0.083, I2 = 36.9%). For P-C treatment, 6 publications with 132 participants were included (Table F in S1 Appendix); the CR was 47.6% (95%CI, 24.8%-71.4%), calculated with the random-effects model (p = 0.000, I2 = 45.3%). No statistically significant difference was found in the CRs of P-S, P-C or TMP-SMX (p = 0.635 in the one-way ANOVA test for 3 independent samples; P = 0.238 in the test of homogeneity of variances). All the details about the therapeutic effects in CRs of these medicines were shown in Fig 3.
3.2.3 The risk of vertical transmission after treatment for the pregnant women’s primary infection of Toxoplasma gondii and the therapeutic efficacies of different drugs for toxoplasmic encephalitis.
For the vertical transmission rate after treatment in the primary infection of pregnant women regardless of gestation age, 11 publications with 3596 participants were included treated with spiramycin alone or combined with P-S (Table G in S1 Appendix); the vertical transmission rate was 9.9% (95%CI, 5.9%-16.2%) with this therapy, which was calculated with the random-effects model (p = 0.000, I2 = 48.6%). This result showed that the chance of vertical transmission was approximately 9.9% when the infected mother received necessary treatment against T. gondii with spiramycin alone or combined with P-S. For the treatment of toxoplasmic encephalitis, 14 publications (Table H in S1 Appendix) with 727 participants were included. The pooled cure rate (CR) of these treatments was 49.4% (95%CI, 37.9%-60.9%), which was calculated with the random-effects model (p = 0.000, I2 = 46.5%). This result showed that approximately 49.4% of toxoplasmic encephalitis would be cured with different therapeutic regimes (Fig 4).
4.1 The efficacy of the therapeutic medicines in the treatment of T. gondii infection
4.1.1 Spiramycin, azithromycin, and traditional Chinese medicine (TCM).
Spiramycin can be absorbed efficiently after oral administration and spreads to blood and tissues quickly, and there has been no evidence that spiramycin is teratogenic, so it can be used in the treatment of T. gondii infection in the general population and women in the first trimester of pregnancy to prevent the vertical transmission . In the 9 included literatures, 5 of which were about the treatment of pregnant women infection, 4 of which were about the treatment of general population including male and female or women at childbearing age (Table A in S1 Appendix). Negative conversion rate (NCR) was used to evaluate the therapeutic efficacy. It was shown that the overall NCR of spiramycin treatment was 84.3% (95%CI: 71.9%-91.8%) in these groups of population.
Azithromycin was used less than spiramycin because of its potential liver toxicity . In the 4 included literatures, 1 of them was about the therapy of the women at childbearing age, 2 of them were about the therapy of infant and child under 14 years old, 1 of male and female aged from 3–58 years (Table B in S1 Appendix). The pooled NCR was used to evaluate the therapeutic efficacy of azithromycin, which was 82.5% (95%CI, 75.9%-87.6%) in our study. As a new generation of macrolide, azithromycin can reduce the sequelae rate among the infected infants at age 1 year , and was widely used in the treatment of refractory ocular toxoplasmosis .
Artemisia annua was shown to reduce the number or density of T. gondii tachyzoites in host cells in vitro and in vivo [8, 26, 27]. Other herbs, including Phellodendron chinense, Hedyotis diffusa, rhizoma Anemarrhenae asphodeloides, radix Sophorae flavescentis, fructus Amomum tsaoko, radix Astragalus membranaceus, Semen arecae, cortex Moutan radicis Poria cocos, Glycyrrhiza uralensis, Rheum palmatum were reported to be able to kill T. gondii tachyzoites and tissue cyst bradyzoites in different combination in host cells and in mice [28–34]. These herbs are the basic ingredients in formulations for anti-T. gondii TCMs. Along with these active ingredients, other personalised conditioning herbs are usually included in TCM treatments to enhance the immune response of the patient. In this study to evaluate the treatment efficacy of TCM against T. gondii infection, 7 literatures were included (Table C in S1 Appendix, Fig 2); the population involved children under 14 years old, men, women, and pregnant women. The pooled NCR of these TCMs was 85.5% (95%CI, 71.3%-93.3%). It was reported that a combination of antibiotics and TCMs for treatment of T. gondii infections showed a 100% NCR in 359 cases after 3 periods of treatment for 30 days [35, 36]. Controlled studies are needed to determine if well-defined formulations of the herbs used in TCM have activity against T. gondii, and it is also required to chemically define the active ingredients.
In the treatment for T. gondii infection in immune competent people which usually are asymptomatic, negative conversion rate is possible for the evaluation of the treatment efficacy. From the included literatures, we found that spiramycin, azithromycin and TCM were mostly used in the treatment of the infection in immune competent population. When they were used alone in treatment of T. gondii infection, no statistical difference was observed in the therapeutic efficacy of these medicines.
4.1.2 pyrimethamine-sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX) and pyrimethamine-clindamycin (P-C).
Cure rate (CR) was used to evaluate the therapeutic efficacy for the treatment of toxoplasmosis. In our study, all the included literatures for P-S, TMP-SMX, and P-C treatment were about toxoplasmic encephalitis in AIDS patients except one in P-C treatment, which was about the acute toxoplasmic encephalitis (Table D, E, F in S1 Appendix). The pooled CRs for P-S treatment was 49.8% (95%CI, 38. 8% -60.8%), for TMP-SMX treatment was 59.9% (95%CI, 48.9%-70.0%), and 64.7% (95%CI, 51.7%-75.8%) for P-C treatment, and no statistically significant difference was found in the CRs of P-S, P-C or TMP-SMX in toxoplasmic encephalitis therapy. It had been reported in a clinical treatment comparison that there was no statistically significant difference in efficacy during acute therapy between P-S and P-C, while P-C treatment got a relapse rate twice as high among patients comparing to P-S treatment . A systematic review for assessment of the efficacy of different treatment regimens in toxoplasmic encephalitis with the randomized clinical trials showed that efficacy of P-S and TMP-SMX were similar, whereas P-S versus P-C showed no difference , which was consistent with our analysis. TMP-SMX suppresses the proliferation of the occasional parasites that emerge from tissue cysts . Pyrimethamine acts on the folatebiosynthesis pathway, inhibiting dihydrofolate reductase activity and thus eventually blocking nucleic acid synthesis . Pyrimethamine in combination with sulfadiazine is effective at inhibiting intracellular T. gondii . From our study, the pooled cure rates of TMP-SMX and P-C were relatively higher than that of P-S in the treatment of toxoplasmic encephalitis. However, it was recommended that P-S is the best choice of treatment, because treatment with TMP-SMX and P-C had a higher recurrence rate, and P-C has more side-effects than P-S [17, 41, 42].
4.2 The efficacy of the different drugs in the treatment of T. gondii infection in different groups of people
4.2.1 The risk of vertical transmission after treatment for the pregnant women’s primary infection of Toxoplasma gondii.
Some studies showed that the risk of congenital toxoplasmosis is reduced in different degree when prenatal treatment was started early in pregnancy [15, 43, 44]. On the contrary, the SYROCOT found no evidence that prenatal treatment significantly reduced the risk of clinical manifestations in infected live born infants . Despite this contradiction, most of the related studies showed that increasing gestational age was strongly associated with increased risk of mother-to-child transmission whatever treated or not [15,45].
Spiramycin had been recommended in the treatment for suspected or confirmed acute T. gondii infection in women during the first 18 weeks of gestation, and could reduce the vertical transmission rate [22, 46, 47], but the treatment medicine should be switched to pyrimethamine-sulfadiazine (P-S) added with folinic acid after 18 weeks of gestation . One reason is that the risk of fetal infection increased with the gestation age, as the placental barrier in later trimesters is less efficient than at the beginning of pregnancy . The other reason is because spiramycin cannot pass through the placenta to the foetus, the treatment of intrauterine infections is not efficient [50, 51]. Generally speaking, rapid initiation of therapy to the infected pregnant women is still important, because fetus infection follows shortly after the mother infection . If foetal infection was confirmed by amniocentesis diagnosis, or if the mother was infected in late pregnancy and there was a high risk of intrauterine infection, P-S with folic acid or its derivatives should be used to the reduce the risk of congenital toxoplasmosis [50, 51].
In our study, to know about the risk of vertical transmission after therapy, the included literatures were 3 papers about spiramycin alone, 5 about the combination of spiramycin and P-S, and 3 about the combination of spiramycin and P-S and folinic acid. It was shown that the mother-to-child transmission rate was 9.9% (95%CI, 5.9%-16.2%) after treatment in primary infection regardless of gestation age. Romand S reported that the overall rate of congenital transmission in maternal infection of T. gondii regardless of gestational age was about 28%, and 97% of the maternal infection had been treated with spiramycin. The difference of the vertical transmission rates between our study and Romand S’ study may due to the different drugs used in treatment and the included samples. All of the samples in our study were treated with spiramycin alone or combined with P-S, while in Romand S’ study, the samples were treated or not with spiramycin. Because the papers included in our study are about patients who received treatment, we don’t know the vertical transmission rate of patients who did not receive any treatment. Randomized and control studies are needed to determine the efficacy of treatment in reducing the mother-to-child transmission rate.
4.2.2 The therapeutic efficacies of different drugs for toxoplasmic encephalitis in AIDS patients.
In the 14 included papers for the treatment of toxoplasmic encephalitis in AIDS patients, pyrimethamine-sulfadiazine (P-S) was used in 8 papers, pyrimethamine-clindamycin (P-C) was adopted in 5 papers, trimethoprim-sulfamethoxazole (TMP-SMX) was used in 3 papers, clindamycin alone, pyrimethamine-azithromycin and atovaquone alone were used in 1 paper respectively. The overall cure rate (CR) of toxoplasmic encephalitis in AIDS patients was only 49.4% with different therapeutic regimes, which may due to the inability of the anti-T.gondii medicines to cross the blood-brain barrier and reach the central nervous system. P-S and TMP-SMX had apparent effects, though limited, on primary prevention (chemoprophylaxis to prevent first episodes of opportunistic infections) of toxoplasmosis in AIDS patients with mild allergic reactions and side-effects . Very few drugs were efficient in secondary prevention (chronic maintenance therapy) of toxoplasmic encephalitis, and P-S was commonly used in this situation . Azithromycin alone or combined with pyrimethamine or SMZ-TMP was also a relatively safe and effective choice for secondary prevention when P-S was unavailable or contraindicated .
The efficacies of spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine-sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin combination (P-C) to treat T. gondii infections were examined in this meta-analysis. Generally speaking, spiramycin, azithromycin and TCM were commonly used in the therapy of general populations infected with T. gondii, had a negative conversion rate of 83.4% (95%CI, 72.1%-90.8%), 82.5% (95%CI, 75.9%-87.6%), and 85.5% (95%CI, 71.3%-93.3%), respectively, and no statistical difference was found between these medicines in therapeutic efficacy. P-S, TMP-SMX and P-C were usually used in the therapy of toxoplasmic encephalitis with the cure rates (CR) of 49.8% (95%CI, 38. 8% -60.8%), 59.9% (95%CI, 48.9%-70.0%), and 47.6% (95%CI, 24.8%-71.4%), respectively, and these were also not significantly different in statistics. Primary infection of T. gondii in pregnant women were treated mainly with spiramycin alone or combined with P-S and/or folic acid, and the vertical transmission was 9.9% (95%CI, 5.9%-16.2%) after therapy. Sulfonamides combined with other drugs were mostly used in the treatment of toxoplasmic encephalitis in AIDS patients; however, the pooled CR was only 49.4% (95%CI, 37.9%-60.9%) in different therapeutic regimes.
S1 Checklist. PRISMA 2009 checklist for the manuscript.
S1 Appendix. Details of each analysis and references of 41 included literatures.
Characteristics of the individual studies included in spiramycin treatment (Table A). Characteristics of the individual studies included in azithromycin treatment (Table B). Characteristics of the individual studies included in traditional Chinese medicine treatment group (Table C). Characteristics of the individual studies included in pyrimethamine- sulfadiazine (P-S) treatment (Table D). Characteristics of the individual studies included in trimethoprim-sulfamethoxazole (TMP-SMX) treatment (Table E). Characteristics of the individual studies included in pyrimethamine-clindamycin (P-C) treatment (Table F). Details of included studies about the risk of vertical transmission after the treatment of primary Toxoplasma gondii infection in pregnant women (Table G). Characteristics of the individual studies included in the treatment of toxoplasmic encephalitis in AIDS patients (Table H).
Conceived and designed the experiments: HJP DSL. Performed the experiments: HXW SSW. Analyzed the data: HXW SSW. Contributed reagents/materials/analysis tools: HXW SSW. Wrote the paper: HXW SSW HJP DSL.
- 1. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004; 363(9425):1965–1976. pmid:15194258
- 2. Robert-Gangneux F, Murat JB, Fricker-Hidalgo H, Brenier-Pinchart MP, Gangneux JP, Pelloux H. The placenta: a main role in congenital toxoplasmosis? Trends Parasitol. 2011; 27(12):530–536. pmid:22079164
- 3. Moncada PA, Montoya JG. Toxoplasmosis in the fetus and newborn: an update on prevalence, diagnosis and treatment. Expert review of anti-infective therapy J. 2012; 10(7):815–828.
- 4. Cottrell AJ. Acquired Toxoplasma encephalitis. Arch Dischild. 1986; 61: 84–85.
- 5. Israelski DM, Remington JS. Toxoplasmosis in non-AIDS immunocopromised host. Curr Clin Top Infect Dis. 1993; 13: 322–356. pmid:8397917
- 6. Luft B J, Hafner R, Korzun AH, Leport C, Antoniskis D, Bosler EM, et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team. NEJM. 1993; 329: 995–1000.
- 7. McLeod R, Kieffer F, Sautter M, Hosten T, Pelloux H. Why prevent, diagnose and treat congenital toxoplasmosis? Mem Inst Oswaldo Cruz. 2009; 104: 320–44. pmid:19430661
- 8. Li Y, Wu YL. How Chinese scientists discovered qinghaosu (artemisinin) and developed its derivatives? What are the future perspectives? Med Trop (Mars). 1998; 58(3 Suppl): 9–12.
- 9. Chen SX, Wu L, Jiang XG, Feng YY, Cao JP. Anti-Toxoplasma gondii activity of GAS in vitro. J Ethnopharmacol. 2008; 118(3):503–7. pmid:18602775
- 10. Yang X, Huang B, Chen J, Huang S, Zheng H, Lun ZR, et al. In vitro effects of aqueous extracts of Astragalus membranaceus and Scutellaria baicalensis GEORGI on Toxoplasma gondii. Parasitol Res. 2012; 110: 2221–2227. pmid:22179265
- 11. Desmonts G, Couvreur J. Toxoplasmosis in pregnancy and its transmission to the fetus. Bull N Y Acad Med. 1974; 50:146–159. pmid:4521728
- 12. Avelino MM, Amaral WN, Rodrigues IM, Rassi AR, Gomes MB, Costa TL, et al. Congenital toxoplasmosis and prenatal care state programs. BMC Infect Dis. 2014; 14:33. pmid:24438336
- 13. Valentini P, Buonsenso D, Barone G, Serranti D, Calzedda R, Ceccarelli M, et al. Spiramycin/cotrimoxazole versus pyrimethamine/sulfonamide and spiramycin alone for the treatment of toxoplasmosis in pregnancy. J Perinatol. 2015; 35(2):90–4. pmid:25211284
- 14. Rodrigues IM, Costa TL, Avelar JB, Amaral WN, Castro AM, Avelino MM. Assessment of laboratory methods used in the diagnosis of congenital toxoplasmosis after maternal treatment with spiramycin in pregnancy. BMC Infect Dis. 2014; 14:349. pmid:24961630
- 15. SYROCOT (Systematic Review on Congenital Toxoplasmosis) study group, Thiebaut R, Leprout S, Chene G, Gilbert R. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients’ data. Lancet. 2007; 369:115–122. pmid:17223474
- 16. Fung HB, Kirschenbaum HL. Treatment Regimens for Patients with Toxoplasmic Encephalitis. Clin Ther. 1996; 18: 1037–1056. pmid:9001822
- 17. Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumech N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis. 1996; 22: 268–275. pmid:8838183
- 18. Harrell M, Carvounis PE. Current treatment of toxoplasma retinochoroiditis: an evidence-based review. J Ophthalmol. 2014; 2014:273506. pmid:25197557
- 19. Gilbert RE, See SE, Jones LV, Stanford MS. Antibiotics versus control for Toxoplasma retinochoroiditis (Review). Cochrane Database Syst Rew. 2002; (1): CD002218.
- 20. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009; 6(6): e1000097.
- 21. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–1558. pmid:12111919
- 22. Tamaru S, Kikuchi A, Takagi K, Wakamatsu M, Horikoshi T, Ogiso Y. Fetal therapy of severe symptomatic toxoplasmosis using azithromycin. J Obstet Gynaecol Res. 2011; Jul;37(7):953–7. Epub 2011 Mar 31. pmid:21450026
- 23. Periti P, Mazzei T, Mini E, Novelli A. Adverse effects of macrolide antibacterials. Drug Saf. 1993; Nov;9(5):346–64. pmid:8280403
- 24. Foulon W, Villena I, Stray-Pedersen B, Decoster A, Lappalainen M, Pinon JM, et al. Treatment of toxoplasmosis during pregnancy: a multicenter study of impact on fetal transmission and children's sequelae at age 1 year.Am J Obstet Gynecol. 1999; 180:410–415. 15. pmid:9988811
- 25. Rothova A, Bosch-Driessen LE, van Loon NH, Treffers WF. Azithromycin for ocular toxoplasmosis. Br J Ophthalmol. 1998; 82: 1306–1308. pmid:9924338
- 26. Yin WD, Gao QC, Liu XD, Tang HW. In vivo Effect of Dihydroartemisinin and azithromycin on the Ultrastructure of Toxoplasma gondii Tachyzoites. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 2009; 27:325–7. pmid:20066989
- 27. Nagamune K, Beatty WL, Sibley LD. Artemisinin induces calcium-dependent protein secretion in the protozoan parasite Toxoplasma gondii. Eukaryot Cell. 2007; 6: 2147–56. pmid:17766463
- 28. Deng JH, Fu L, Chen YS, Guo HF, Zhang JL. The soup of toxoplasmosis to treating 50 cases with toxoplasmosis in children. Journal of Traditional Chinese Medicine. 1996; 37: 102–103.
- 29. Wang CG. The research of treating toxoplasmosis using Artemisia annua and preliminary observations clinical treatment. Chinese Journal of Zoonoses. 1997; 13: 79–80.
- 30. Qi GC, Li QX, Kan QL, Tong HW, Zhang GZ, Xu WY, et al. The analysis of clinical curative effects of Qing Jing Granules on toxoplasmosis of 42 cases with infertility. Journal of Traditional Chinese Medicine. 1999; 40: 603–605.
- 31. Mi Y, Mi C. The treating of 70 cases toxoplasmosis in pregnancy using Astragalusannua. Shandong Journal of Traditional Chinese Medicine. 2000; 19: 83–84.
- 32. Sun YX, Niu HZ, Yu LX. Righting Disinfection Treatment 60 cases toxoplasmosis of women in childbearing age. Chinese Journal of Integrated Traditional and Western Medicine. 2001; 467–468.
- 33. Tian C, Wang WH, Yuan XH, Ren LJ, Zhang XB, Zhang XM. The clinical study of righting eliminate the original pill on toxoplasmosis. Shandong Journal of Traditional Chinese Medicine. 2004; 23: 528–529.
- 34. Li DH, Li YG, Zhang WJ. Clinical studies on the treatment of toxoplasmosis by the anti- toxoplasmosis decoction. Journal of Pathogen Biology. 2011; 6: 295–296.
- 35. Ou YW, Li M. Analysis the detection and treat of toxoplasma infection in women of childbearing age. Liuzhou Medicine. 2009; 22: 56.
- 36. Wang XQ, Zhu Q. The analysis of curative effects of 192 cases with toxoplasmosis. Occupation and Health. 2005; 04: 612–613.
- 37. Rajapakse S, Chrishan Shivanthan M, Samaranayake N, Rodrigo C, Deepika Fernando S. Antibiotics for human toxoplasmosis: a systematic review of randomized trials. Pathog Glob Health. 2013; 107(4):162–169. pmid:23816507
- 38. Felix JP, Lira RP, Zacchia RS, Toribio JM, Nascimento MA, Arieta CE. Trimethoprim-Sulfamethoxazole Versus Placebo to Reduce the Risk of Recurrences of Toxoplasma Gondii Retinochoroiditis: Randomized Controlled Clinical Trial. American Journal of Ophthalmology. 2014; 157(4): 762–766.e1. pmid:24388839
- 39. Romand S, Pudney M, Derouin F. In vitro and in vivo activities of the hydroxynaphthoquinone atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, or minocycline against Toxoplasma gondii. Antimicrob Agents Chemother. 1993; 37(11): 2371–8. pmid:8285620
- 40. Chang HR, Jefford CW, Pechère JC. In vitro effects of three new 1,2,4-trioxanes (pentatroxane, thiahexatroxane, and hexatroxanone) on Toxoplasma gondii. Antimicrob Agents Chemother. 1989; 33(10): 1748–52. pmid:2589842
- 41. Chirgwin K, Hafner R, Leport C, Remington J, Andersen J, et al. (2002) Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/AgenceNationale de Recherchesur le SIDA, Essai 039. Clin Infect Dis 34:1243–1250. pmid:11941551
- 42. Beraud G, Pierre-Francois S, Foltzer A, Abel S, Liautaud B, Smadja D, et al. Cotrimoxazole for treatment of cerebral toxoplasmosis: an observational cohort study during 1994–2006. Am J Trop Med Hyg.2009; 80: 583–587. pmid:19346380
- 43. Cortina-Borja M, Tan HK, Wallon M, Paul M, Prusa A, Buffolano W, et al. Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observation prospective cohort study. PLoS Med. 2010; 7:e1000351. pmid:20967235
- 44. Gras L, Wallon M, Pollak A, Cortina-Borja M, Evengard B, Hayde M, et al. Association between prenatal treatment and clinical manifestations of CT in infancy: a cohort study in 13 European centres.Acta Paediatr. 2005; 94: 1721–1731 pmid:16421031
- 45. Wallon M, Peyron F, Cornu C, Vinault S, Abrahamowicz M, Kopp CB, et al. Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years. Clin Infect Dis. 2013; 56(9):1223–31. pmid:23362291
- 46. Meroni V, Genco F, Tinelli C, Lanzarini P, Bollani L, Stronati M, et al. Spiramycin treatment of Toxoplasma gondii infection in pregnant women impairs the production and the avidity maturation of T. gondii-specific immunoglobulin G antibodies. Clin Vaccine Immunol. 2009; 16(10):1517–20. pmid:19692628
- 47. Montoya JG, Remington JS. Management of Toxoplasma gondii Infection during Pregnancy. Clinical Infectious Diseases. 2008; 47:554–66. pmid:18624630
- 48. Berrebi A, Bardou M, Bessieres MH, Nowakowska D, Castagno R, Rolland M, et al. Outcome for children infected with congenital toxoplasmosis in the first trimester and with normal ultrasound findings: a study of 36 cases. Eur J Obstet Gynecol Reprod Biol. 2007; 135:53–57. pmid:17189666
- 49. Rabilloud M, Wallon M, Peyron F. In utero and at birth diagnosis of congenital toxoplasmosis: use of likelihood ratios for clinical management. Pediatr Infect Dis J. 2010; 29(5):421–5. pmid:19952858
- 50. Montoya JG, Remington JS. Management of Toxoplasma gondii Infection during Pregnancy. Clinical Infectious Diseases. 2008; 47:554–66. pmid:18624630
- 51. Gilbert R, Gras L. Effect of timing and type of treatment on the risk of mother to child transmission of Toxoplasma gondii. BJOG. 2003; 110: 112–20. pmid:12618153
- 52. Romand S, Wallon M, Franck J, Thulliez P, Peyron F, Dumon H. Prenatal diagnosis using polymerase chain reaction on amniotic fluid for congenital toxoplasmosis. Obstet Gynecol. 2001; 97:296–300. pmid:11165598
- 53. Ruf B, Schurmann D, Bergmann F. Efficacy of pyrimethamine/sulfadoxine in the prevention of toxoplasmic encephalitis relapses and Pneumocystis carinii pneumonia in HIV-infected patients. Eur J Clin Microbiol Infect Dis. 1993; 12: 325–329. pmid:8354297
- 54. Jordan MK, Burstein AH, Rock-Kress D, Alfaro RM, Pau AK, Pau AK, et al. Plasma pharmacokinetics of sulfadiazine administered twice daily versus four times daily are similar in human immunodeficiency virusinfected patients. Antimicrobial Agents and Chemotherapy. 2004; 48: 635–637. pmid:14742225
- 55. Duval X, Pajot O, Le Moing V, Longuet P, Ecobichon JL, Mentre F, et al. Maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy. AIDS. 2004; 18: 1473–5571.