TABLE 10

Antepartum and Postnatal Treatment Protocols in the United States for CT, According to the PAMF-TSL and the Toxoplasmosis Center at the University of Chicago

During pregnancy
 Spiramycin (oral)a
  • Recommended for women suspected or confirmed of having acquired their infection at <18 weeks of pregnancy
  • Spiramycin should be administered until delivery in women with negative AF PCR test results and negative follow-up fetal ultrasonographic results or low suspicion of fetal infection
  o Spiramycin is not teratogenic and is available in the United States only through the Investigational New Drug process at the FDA (telephone: 301-796-1600)b
  • Spiramycin dose = 1 g (3 million IU) PO TID
  o Total daily dose = 3 g (9 million IU) per day
  • Consultation with medical consultants familiar with toxoplasmosis is strongly recommended
  • Spiramycin is not recommended during pregnancy if the fetus has been documented to be or suspected to have been infected
  • For fetal infections, maternal treatment with pyrimethamine/sulfadiazine/folinic acid should be instituted (see below)
 Pyrimethaminec + sulfadiazine + folinic acid (oral)b
  • Recommended for women ≥18 weeks of pregnancy for whom (1) it is suspected or confirmed that they acquired acute infection at or after the 18th week of pregnancy, (2) a positive AF PCR test result is documented, or (3) an abnormal fetal ultrasonograph is suggestive of CT
  • Pyrimethamine dosec: 100 mg/day PO divided BID for 2 days followed by 50 mg/day PO QD
  • Sulfadiazine dose: 75 mg/kg per dose PO × 1, followed by 100 mg/kg per day PO divided BID (maximum sulfadiazine = 4 g/day)
  • Folinic acid (leucovorin) dose: 10–20 mg/day PO QD (during and 1 week after pyrimethamine therapy)
  o Folic acid should not be used as a substitute for folinic acid
  o Pyrimethamine is potentially teratogenic and should not be used before the 18th week of pregnancy
  o Sulfadiazine should not be used alone
Infants with CT (treatment regimen is usually recommended for 1 year)
 Pyrimethaminec
  • First 2 days: 2 mg/kg per day PO divided BID for 2 days
  • Intensive initial therapy from day 3 to 2 months (or to 6 months)d: 1 mg/kg per day PO QD (although statistically significant difference was not found between the 2-month versus the 6-month intensive therapy regimen; equivalence between these 2 regimens was not established)
  • Intensive initial therapy for 2 months might be considered in infants with CT who are asymptomatic at birth, whereas continuation of the initial intensive therapy for 6 months might be considered for infants with CT who are symptomatic
  • After the first 2 months (or the first 6 months) of intensive therapy: 1 mg/kg per day PO TIW to complete a total therapy of 12 months (daily + TIW regimen)
 Sulfadiazine
  • 100 mg/kg per day PO divided BID
 Folinic acid (leucovorin)e
  • 10 mg PO TIW
 Prednisone if CSF protein ≥1 g/dL or severe chorioretinitis in vision-threatening macular area (based on expert opinion)
  • 1 mg/kg per day PO divided BID (until CSF protein <1 g/dL or until resolution of severe chorioretinitis) (based on expert opinion, if steroids are to be used, they should be initiated after 72 hours of anti-Toxoplasma therapy)
Older children (diagnosed beyond the neonatal period) with active disease (chorioretinitis)
 Pyrimethamine/sulfadiazinef,g,h (for at least 1–2 weeks after resolution of all signs and symptoms and for ∼4–6 weeks total)
 Pyrimethaminec:
  • First 2 days: 2 mg/kg per day PO divided BID (maximum 50 mg/day)
  • Then: 1 mg/kg per day PO QD (maximum 25 mg/day)
 Sulfadiazine
  • 75 mg/kg/dose PO × 1, followed by 100 mg/kg per day PO divided BID
 Folinic acid (leucovorin)e
  • 10–20 mg PO TIW
 Prednisone (severe chorioretinitis)
  • 1 mg/kg per day divided BID (maximum 40 mg/day; rapid taper) (based on expert opinion)
  • For assistance with the diagnosis and management of infants or children with CT, you can contact the following: Palo Alto Medical Foundation Toxoplasma Serology Laboratory (PAMF-TSL), Palo Alto, CA; www.pamf.org/serology; http://www.pamf.org/serology/testinfo.html; telephone: (650) 853-4828; fax: (650) 614-3292; e-mail; toxolab@pamf.org; and/or Professor Rima McLeod from the Toxoplasmosis Center at the University of Chicago (Center of the National Collaborative Chicago-based Congenital Toxoplasmosis Study [NCCCT]); telephone: (773) 834-4130). Pharmacokinetic data: (1) The pharmacokinetic data of spiramycin during pregnancy studied by Couvreur et al187 in 20 pregnant women revealed that the placental concentration of spiramycin was 4 times the maternal blood concentration (2.3 vs 0.47 mg/L) and the fetal blood concentration was 47% of the maternal blood concentration (0.29 vs 0.68 mg/L); (2) only pharmacokinetic studies in mice were conducted to estimate the pharmacokinetic data for maternal treatment with P/S; and (3) the pharmacokinetic data for maternal treatment with pyrimethamine/sulfadoxine (Fansidar) studied by Dorangeon et al188 showed that the levels of pyrimethamine in the newborn infant at the time of delivery were 50% to 100% of maternal blood levels and the levels of sulfadoxine were 100% of the maternal blood level. The pharmacokinetic data for infants’ treatment with pyrimethamine/sulfadoxine (Fansidar) studied by Corvaisier et al,189 did not establish the concentration of the pyrimethamine/sulfadoxine that is most efficacious in treating children with CT. They studied 32 infants with CT receiving pyrimethamine/sulfadoxine every 10 days for 1 year, and 101 measurements were collected. Even when the dose was standardized for body weight, the difference of the pyrimethamine minimum and maximum concentrations ranged between 8- and 25-fold and for sulfadoxine between fourfold and fivefold. There is a need for future studies to address the association between long-term clinical outcomes in children with CT and the pharmacokinetic parameters of these drugs. BID, twice per day; PO, by mouth; QD, daily; TID, 3 times per day; TIW, 3 times per week.

  • a Acquisition of spiramycin in the United States: Spiramycin is not commercially available in the United States. It can be obtained at no cost and after consultation (with PAMF-TSL, telephone 650-853-4828, or the NCCCT, telephone 773-834-4152, through the US FDA, telephone 301-796-1600). Through this program, Sanofi-Aventis, for many years, has been providing spiramycin at no cost.

  • b Experience from the antepartum treatment strategies used in Germany: In Germany, where a different antepartum treatment approach is used,4 a very low overall transmission rate of 4.8% has been documented, compared with an overall transmission risk in other Western European cohort studies of ∼30% (for T gondii infections across all trimesters).2,94 The reported transmission risks in Germany according to the time of maternal primary infection during pregnancy were 1.3% (6 of 479 children) for the first trimester, 10.6% (17 of 160 children) for the second trimester, and 21.7% (10 of 46 children) for the third trimester.4 Prenatal treatment approach in Germany: Once acute T gondii infection is diagnosed during pregnancy, spiramycin is administered until up to the 16th week of pregnancy. However, after the 16th week, treatment is changed to P/S plus folinic acid in all women and for at least 4 weeks until performance of T gondii AF PCR assay and independently of fetal infection status. Subsequently, if fetal ultrasonography indicates congenital infection or if the AF PCR result is positive for T gondii, treatment with P/S is continued until delivery (otherwise, it is subsequently changed back to spiramycin prophylaxis). Therefore, all women with acute T gondii infection during pregnancy will be treated also with at least 4 weeks of combination therapy. Screening during the second and third trimester occurs less frequently than screening during the first trimester, because there is no mandatory routine antepartum screening program during pregnancy.

  • c Acquisition of pyrimethamine: As of June 2015, pyrimethamine is no longer available in retail pharmacies in the United States. It is only available through a special pharmacy program at Walgreens (http://www.daraprimdirect.com/how-to-prescribe). After a physician prescribes pyrimethamine, he or she will need to fill out a patient Prescription & Enrollment form (http://www.daraprimdirect.com/forms/Daraprim-Prescription-Form.pdf) and fax it to Walgreens Specialty Pharmacy. From there, a dedicated representative for this drug will contact the patient to arrange for the prescription to be delivered. For questions about the pyrimethamine prescription, call this toll-free number: 1-800-222-4991. Medication will be delivered to the patient on the same day if marked in the enrollment form as “STAT/URGENT.” The medication should be provided/sent directly to the patient or his/her physician without any delays for insurance clearance. In this form you may add: “Request for no delay in the delivery of medication for insurance clearance.” For patients without insurance, the medicine will be made available without charge by the company (after completion of the relevant form at the link above).

  • d Comparative efficacy of the initial daily treatment of 2 months versus the 6-month initial regimen: This was tested in the context of an RCT by the NCCCT study group.110 Although this RCT did not show a statistically significant difference between the 2 treatment arms, the study was not powered to detect a small to modest difference in relative reduction in outcomes (eg, a difference <60%); thus, the absence of a detected statistically significant difference does not also mean that the 2 arms are equivalent in efficacy. Children in this study who had begun treatment at 2.5 months of age had completed the 12-month therapy course at 14.5 months of age. In the recently published data from the Lyon cohort,137 there were also children with CT who were treated with pyrimethamine and sulfonamides for >12 months; the median duration of treatment was 15 months, but the interquartile range was 12 to 19 months. In the Toulouse cohort, children were treated until 24 months of age.129

  • e Folic acid should not be used as a substitute for folinic acid (leucovorin).

  • f Treatment options of acute toxoplasmic chorioretinitis in children: There are no comparative pediatric trials on the relative efficacy of different treatment regimens for acute toxoplasmic chorioretinitis. In the adult literature there are also only a few comparative trials (eg, comparison of intravitreal clindamycin plus dexamethasone versus PO P/S,190 azithromycin versus P/S,191 or trimethoprim/sulfamethoxazole versus P/S192) and there is lack of high-quality evidence to determine the best treatment option.193 In immunocompetent adults, many observational studies suggest a benefit of short-term antimicrobial therapy.194 Some experts in the United States, as an alternative to the classic treatment option of P/S, have also tried short-term antimicrobial therapy in children with toxoplasmic chorioretinal lesions that are not in a vision-threatening area, alternative combinations such as pyrimethamine plus clindamycin or azithromycin, and then continuation with clindamycin or azithromycin alone.107 However, there is no systematic published experience with those alternative treatment options.

  • g Duration of anti-Toxoplasma therapy for acute toxoplasmic chorioretinitis: There are no comparative trials in children or in adults for the relative efficacy of different treatment durations for ocular toxoplasmosis. On the basis of experience in adult patients, anti-Toxoplasma treatment may be considered to be continued for at least 1 to 2 weeks after resolution of clinical signs and symptoms of acute chorioretinitis (with sharpening of the lesion borders and/or scarring of the lesion) and for ∼4 to 6 weeks total.195,196 (Although often the acute eye disease resolves within 10 to 14 days after initiation of treatment, there are cases that take a longer time to resolve). Longer treatment durations have also been proposed with courses up to 3 months in children with P/S, on the basis of French experience,137,184 and up to 4 months in adults.194 Close ophthalmologic follow-up every 2 to 3 weeks is necessary in all cases of active Toxoplasma chorioretinitis to determine optimal duration of treatment.

  • h Anti-Toxoplasma prophylaxis for the prevention of recurrent eye disease in infants with CT: There are no randomized clinical trials addressing the efficacy of postnatal prophylaxis to prevent recurrent eye disease in children with CT before their first recurrence. The reported rates of recurrence of eye disease vary according to the presence or absence of antepartum treatment and the presence or absence of postnatal treatment. A placebo-controlled, open-label RCT in Brazil by Silveira et al197 on prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) in 124 patients with a history of recurrent Toxoplasma chorioretinitis found that prophylactic TMP/SMX (TIW) for 20 months was associated with a 75% decrease in the risk of recurrence of eye disease (HR: 0.25; 95% CI: 0.08–0.75). The median age of the enrolled subjects in this trial was 26 years, and no infants were enrolled. Although children as young as 7 years of age were included, the exact number of such subjects was not reported.197 Another RCT also found that prophylactic TMP/SMX in adults from Brazil (N = 95) decreased the risk of recurrence by 100% within 12 months of prophylaxis198 (0 of 46 [0%] and 6 of 47 [12.80%] in the TMP/SMX and placebo groups, respectively; P = .026). For young adolescents with recurrences of eye disease during puberty, some experts in the United States have also tried the use of azithromycin as a suppressive therapy for several months. Nevertheless, data on the use of azithromycin for Toxoplasma chorioretinitis are very sparse (both from human studies191,199 and from studies in animal models200). Alternative approach to anti-Toxoplasma prophylaxis: home/self-monitoring for any signs and symptoms of decreased visual acuity, daily monitoring of visual acuity using home vision test methods (eg, Allen card pictures, print-outs of newspapers, etc), and prompt referral to an ophthalmologist if new symptoms occur are suggested so that treatment can be promptly initiated for any recurrence.107 As previously discussed, the risk of recurrence of eye disease in the United States: Where the majority of the infants with CT had mothers who were not treated during pregnancy, recurrent eye disease developed in 72% of children with CT who were diagnosed after their first year of life and thus were not postnatally treated (18 of 25; 95% CI: 51%–89%).107 For comparison, recurrent eye disease developed in only 31% (34 of 108; 95% CI: 23%–41%) of US infants with CT who had received 12 months of postnatal treatment during their first year of life.108 The risk of recurrence of eye disease in Brazil: In a cohort of 30 infants from Brazil with CT diagnosed by neonatal screening, the risk of recurrence of eye disease was 43%37 (vs 29% in 281 children with CT from European cohorts in that study). The risk of recurrence of eye disease in the Lyon cohort: The risk of recurrence of eye disease and within 12 years after the diagnosis of the first eye lesion was ∼34%.137 Of note, infants in the Lyon cohort had mothers who were treated during pregnancy and the infants were also postnatally treated.