Document Detail

Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy.
Jump to Full Text
MedLine Citation:
PMID:  22321288     Owner:  NLM     Status:  MEDLINE    
The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.
Julie Gutman; S Patrick Kachur; Laurence Slutsker; Alexis Nzila; Theonest Mutabingwa
Related Documents :
6163148 - Pregnancy-associated plasma protein-a: an inhibitor of the complement system.
6400658 - Pregnancy alters diurnal variation of plasma glucose concentration.
6684078 - Changes in the diurnal rhythms of plasma cortisol in women during the third trimester o...
21787448 - Impact of maternal supplementation with probiotics during pregnancy on atopic eczema in...
9526688 - A method for regulating the duration of pregnancy and the time of parturition in spragu...
21852198 - Neurologists' and neurology residents' knowledge of issues related to pregnancy for wom...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2012-02-09
Journal Detail:
Title:  Malaria journal     Volume:  11     ISSN:  1475-2875     ISO Abbreviation:  Malar. J.     Publication Date:  2012  
Date Detail:
Created Date:  2012-03-07     Completed Date:  2012-05-11     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101139802     Medline TA:  Malar J     Country:  England    
Other Details:
Languages:  eng     Pagination:  39     Citation Subset:  IM    
Copyright Information:
© 2012 Gutman et al; BioMed Central Ltd.
Division of Parasitic Diseases & Malaria, Malaria Branch, 1600 Clifton Rd. NE, Mailstop A06, Atlanta, GA 30329, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Antimalarials / administration & dosage*,  adverse effects,  pharmacokinetics
Chemoprevention / adverse effects,  methods*
Drug Combinations
Drug Therapy, Combination / adverse effects,  methods
Malaria, Falciparum / drug therapy,  prevention & control*
Pregnancy Complications, Infectious / drug therapy,  prevention & control*
Probenecid / administration & dosage*,  adverse effects,  pharmacokinetics
Pyrimethamine / administration & dosage*,  adverse effects,  pharmacokinetics
Sulfadoxine / administration & dosage*,  adverse effects,  pharmacokinetics
Treatment Outcome
Grant Support
Reg. No./Substance:
0/Antimalarials; 0/Drug Combinations; 2447-57-6/Sulfadoxine; 37338-39-9/fanasil, pyrimethamine drug combination; 57-66-9/Probenecid; 58-14-0/Pyrimethamine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Malar J
ISSN: 1475-2875
Publisher: BioMed Central
Article Information
Download PDF
Copyright ©2012 Gutman et al; BioMed Central Ltd.
Received Day: 2 Month: 11 Year: 2011
Accepted Day: 9 Month: 2 Year: 2012
collection publication date: Year: 2012
Electronic publication date: Day: 9 Month: 2 Year: 2012
Volume: 11First Page: 39 Last Page: 39
ID: 3295670
Publisher Id: 1475-2875-11-39
PubMed Id: 22321288
DOI: 10.1186/1475-2875-11-39

Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy
Julie Gutman1 Email:
S Patrick Kachur1 Email:
Laurence Slutsker2 Email:
Alexis Nzila3 Email:
Theonest Mutabingwa4 Email:
1Division of Parasitic Diseases & Malaria, Malaria Branch, 1600 Clifton Rd. NE, Mailstop A06, Atlanta, GA 30329, USA
2Center for Global Health, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mailstop D-69, Atlanta, GA 30329-4018, USA
3Department of Chemistry, King Fahd University of Petroleum and Minerals, PO Box 468, Dhahran, 31261, Saudi Arabia
4Department of Community Medicine, Hubert Kairuki Memorial University, Dar-es-Salaam, Tanzania

Decreasing efficacy of sulphadoxine-pyrimethamine for intermittent prevention of malaria in pregnancy

The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention and treatment of malaria in pregnancy; in addition, it has been explored for intermittent preventive treatment (IPT) in infants and children [1-7]. SP is an ideal choice for intermittent preventive treatment in pregnancy (IPTp), as it is effective as a single dose given two to three times in pregnancy, with an interval of at least one month between doses. Data from Mali suggest that three doses are significantly more effective than two doses [8]. Resistance of Plasmodium falciparum to SP has been increasing, and its use is no longer recommended for treatment of malaria in Africa [9-11]. In some areas where SP is no longer an effective malaria therapy, IPTp with SP has been shown to be beneficial to HIV-uninfected pregnant women, possibly as a result of their pre-existing immunity [1]. Of concern, however, is a recent report from Muheza, an area of Tanzania with high level SP resistance, suggesting that its use for IPTp may exacerbate resistance [12]. In that study, SP-IPTp was associated with a 5.4% increase (p = 0.003) in the prevalence of parasitaemia in women who reported SP-IPTp use compared to those who did not. In addition, women who reported SP-IPTp use had both a higher prevalence of placental inflammation by histopathology and higher intensity of inflammation than women who did not report using SP-IPTp [12]. A subsequent study from the same area showed the lack of beneficial pregnancy outcomes from SP-IPTp [13]. Data from Malawi also show that the effectiveness of SP-IPTp has been decreasing over time and no longer appears to provide any benefit [14]. In view of these findings, it is critical to search for new agents for IPTp; mefloquine or azithromycin-based combinations (including azithromycin plus chloroquine) currently appear most promising [15]. While searching for alternatives to SP-IPTp, data from in vitro experiments have shown that probenecid can increase the activity of the anti-malarial antifolates [16,17]. Furthermore, malaria treatment studies in Nigerian children have shown that the addition of probenecid increases the treatment efficacy of SP [18,19]. Implicitly, the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp.

Mechanism of action and development of resistance to SP

Sulphadoxine and pyrimethamine act synergistically to inhibit two steps in the folate synthesis pathway. Sulphadoxine inhibits the enzyme dihydropteroate synthetase (dhps) while pyrimethamine inhibits the enzyme dihydrofolate reductase (dhfr). Resistance develops in a step-wise manner due to a combination of mutations in these genes, with increasing numbers of mutations conferring increasing levels of resistance [20]. This results in an increased minimal inhibitory concentration (MIC), which translates to a decreased duration of prophylaxis because as drug levels fall, they reach the point at which they no longer suppress parasite replication sooner (Figure 1) [21]. The presence of the "quintuple mutant" consisting of the dhfr triple mutant (point mutations causing a Ser → Asn change at position 108, Asn → Ile at codon 51, and Cys → Arg at codon 59) and the dhps double mutant (due to point mutations which convert Ala → Gly at codon 437 and Lys → Glu at codon 540) has been most strongly associated with treatment failure [22], although host immunity still plays a significant role in determining drug efficacy [23]. Although theoretically, increasing the dose of SP could potentially overcome resistance to some degree, modelling suggests that increasing the dose of SP dose will only have a marginal benefit since highly resistant parasites will not be efficiently cleared by in vivo drug levels achievable within safety margins [24]. Furthermore, data in pregnant women indicate that there is significant variability in the effect of pregnancy on the disposition of SP, thus it was concluded that it is not possible to recommend an adjustment to the dose of SP to increase its efficacy [25].

Rationale for use of probenecid

Probenecid was developed in 1950 to inhibit the renal tubular secretion of penicillin, increasing the blood concentration of the drug and decreasing the required dose [26,27]. Since its introduction, it has been found to inhibit the tubular secretion of other weak organic acids, such as p-aminohippuric acid, salicylic acid and uric acid, as well as other antibiotics (including cephalosporins), and anti-retrovirals (including oseltamavir and zidovudine). This characteristic of probenecid allows for decreased doses of medications to be used, thus limiting toxicity, especially with nephrotoxic agents [27-30]. Probenecid has been widely used as an uricosuric agent in the treatment of gout [26], and has a long history of use without serious toxicity [31]. It is widely available and inexpensive, costing approximately US$1 per 500 mg tablet.

Probenecid is a substrate for multi-drug resistance-associated protein (MRP) and the uric acid transporter [32] and is an inhibitor of both organic anion transporters 1 and 3 (OAT1 and OAT3) [33-35]. Probenecid increases plasma concentrations of the antifolate methotrexate by inhibiting drug efflux mediated by the MRP family of ATP-binding cassette transporters while at the same time inhibiting folate uptake [36]. This has been shown to reverse some forms of methotrexate resistance, and can increase the anti-cancer efficacy of antifolate drugs (methotrexate analogs) [36,37].

For treatment of P. falciparum infections, studies have clearly demonstrated that the addition of folate derivatives decreases the activity of antifolate drugs, both in vitro and in vivo [38-40]. Likewise, the lowering of folate concentration in vivo enhances the activity of antifolate anti-malarial agents [41]. This, taken together with the data from the studies of methotrexate, suggests that probenecid may be able to increase the efficacy of antifolates against resistant Plasmodium parasites by increasing the concentration of drug and limiting the uptake of folate. This has been demonstrated in vitro for the antifolates sulphadoxine, dapsone, pyrimethamine, and chlorcycloguanil [17]. In the presence of clinically achievable probenecid concentrations (50 μM or 14.268 mcg/ml), the activity of these antifolates was significantly increased. Increased activity ranged from two- to seven-fold, and in the case of resistant parasite isolates, reduced half maximal inhibitory concentrations (IC50) to levels seen in drug sensitive isolates [17]. These improvements in drug susceptibility correlated with reduced folate uptake in the presence of probenecid [17]. Probenecid has also been shown to reverse chloroquine resistance and increase piperaquine activity in vitro [17,42].

Probenecid has been shown to increase the efficacy of SP for the treatment of malaria in clinical trials in Nigerian children in an area with approximately 25% resistance to SP. In a study of 151 children under the age of 12 years, Sowunmi et al. showed that the addition of approximately 20-25 mg/kg/d of probenecid for three-days to standard SP dosing increased the efficacy of SP, as measured by the parasitological cure rate at day 14, compared to children who received SP alone (96.2% vs 83.5%, p = 0.02, n = 78 and 73, respectively) [19]. Although the cure rate in the SP-probenecid group remained higher at day 28, this was no longer statistically significant (79.4% vs 72.6%, p = 0.4) [19]. The combination of SP-probenecid was well tolerated in this small study and had no significant side effects [19]. Similar findings were reported from the same study population, with a 14-day cure rate of 100% in the SP-probenecid arm (n = 5) compared to 88% in the SP arm (n = 25) in one study and 94.8% (n = 39) compared to 76.4% (n = 34, p = 0.02) in another [18,43].

Although probenecid has been in use for over half a century, and has been recommended as part of the treatment of gonorrhea in pregnancy, very little clinical data exist on its safety in pregnancy. Furthermore, no clinical studies have been done on the pharmacokinetics of probenecid in pregnancy. Available evidence suggests that probenecid may potentiate the effect of SP and thus prolong its use for IPTp. However, data from pregnant women are needed to explore this potential. This review presents available data and highlights the knowledge gaps surrounding potential use of SP-probenecid combination as an effective agent for IPTp.


Probenecid is packaged as 500 mg tablets. It is a weak acid (pKa 3.7) [44], and its oral bioavailability is > 90% [45]. In healthy adults, probenecid is 85-95% bound to plasma albumin and has a small apparent volume of distribution of 0.003-0.014 L/kg [44,46]. The maximum adult dose of probenecid is 3 g, and a single oral dose of 2 g (approximate 25 mg/Kg) yields peak plasma concentrations of 150-200 mcg/mL within four hours; concentrations above 50 mcg/mL are sustained for eight hours [31,47]. Following a 2 g dose, the half-life is 4-17 h; the half-life is dose-dependent, decreasing as the dose decreases to 500 mg [31]. Probenecid is metabolized in the liver via oxidation and glucuronidation and is primarily excreted in the urine (75-85%) [27]. No dosage adjustment is necessary for patients with mild renal failure (glomerular filtration rate greater than 50 mL/min); probenecid is not effective in severe renal failure and should be avoided [48,49]. No data are available on the pharmacokinetics of probenecid in pregnant women.

Sulphadoxine-pyrimethamine (SP)

SP is packaged as a fixed dose combination containing 500 mg sulphadoxine and 25 mg pyrimethamine and costs approximately US$1 per treatment (adult dosage is three tablets). In the non-pregnant population, both sulphadoxine and pyrimethamine have an oral bioavailability of > 90%, and are 85-90% protein bound [25]. The volume of distribution for sulphadoxine and pyrimethamine is 0.14 L/kg and 2.3 L/kg, respectively [50]. Oral administration of one tablet yields peak plasma levels of approximately 0.2 mg/L for pyrimethamine and approximately 60 mg/L for sulphadoxine at approximately four hours [50]. Both compounds have a very long half-life; the half-life of sulphadoxine is approximately 169 h (range 100-230 h), while that of pyrimethamine is approximately 111 h (range 54-148 h) [51]. Sulphadoxine is metabolized via glucuronidation and excreted primarily in urine, while pyrimethamine is metabolized to several unidentified metabolites but also excreted primarily in the urine [25,52].

Several studies have examined the pharmacokinetics of SP in pregnant women. All examined the standard dose for IPTp of three tablets (1500 mg of sulphadoxine and 75 mg of pyrimethamine). Nyunt et al. studied women in four African countries both during pregnancy and six to eight weeks post-partum, and found that, at Day 7 following administration of SP, there was an increased blood concentration of pyrimethamine, with an area under the curve (AUC) of 1,906 ng·day/ml during pregnancy vs 849 ng·day/ml postpartum, with geometric mean ratio of pharmacokinetic values between pregnancy and postpartum period 1.38 (1.22-1.56), p-value < 0.0001. In addition, they found decreased concentration of sulphadoxine with an AUC of 877 μg·day/ml during pregnancy versus 884 μg·day/ml postpartum, with geometric mean ratio of pharmacokinetic values between pregnancy and postpartum period 0.88 (0.80-0.96), p-value = 0.004, also on Day 7. However, there was significant variation in the exact pharmacokinetic parameters among the different study sites [25]. Findings from a study done in Kisumu, Kenya by Green et al., looking at levels of SP during pregnancy compared to eight-12 weeks post-partum, found similar results for sulphadoxine [53]. However, pyrimethamine pharmacokinetics were not significantly different in pregnant vs non-pregnant women [53]. In a third study conducted in Papua New Guinea where pregnant women were matched to non-pregnant controls, plasma concentrations of both sulphadoxine and pyrimethamine were found to be lower in the pregnant women compared to the non-pregnant controls (AUC of 22,315 vs 33,284 mg·h/l for sulphadoxine and 72,115 vs 106,065 μg·h/l for pyrimethamine; p-value < 0.001 for both) [54]. These varying results may be due to genetic differences in the women that contribute to differential drug metabolism, as well as to differences in body weight.

There are no data on how the combination of probenecid, sulphadoxine, and pyrimethamine affects pharmacokinetics or pharmacodynamics of the individual drugs. Further studies are needed to define these effects and to determine optimal dosing regimens. Given the significant differences in the half lives of SP and probenecid, there is also a need to optimize the probenecid regimen to maximize efficacy of SP while minimizing the frequency of administration to facilitate adequate compliance and adherence.

Adverse events

Adverse reactions with probenecid are quite rare, occurring in approximately 0.1-0.3% of the general population, although the rate in pregnancy is unknown [55]. While rare, adverse reactions have been reported in almost all organ systems, including gastrointestinal, dermatologic, hematologic, renal, and immunologic (anaphylaxis) [26]. Isolated cases of aplastic anaemia, leukopenia, neutropenia, and thrombocytopenia have been reported [56]. Early reports suggested that probenecid may be associated with haemolysis in individuals with glucose-6-phosphatase dehydrogenase (G6PD) deficiency [57]. However, this has not been shown to be the case in subsequent studies [58,59]. Furthermore, recent reviews report that probenecid is not likely to cause haemolysis in patients with G6PD deficiency [60,61]. Probenecid has, however, been associated with immune mediated haemolytic anaemia in several case reports [62,63]. Nephrotic syndrome, which typically resolves on removal of drug, has been reported in a very small number of cases, with one case progressing to death [64-68]. There has also been a single case report of fatal haepatic necrosis [69]. Hypersensitivity reactions to probenecid in the general population may occur in as many as 2% to 4%. The incidence of probenecid hypersensitivity is much higher in HIV-infected patients ranging from 11% to 25% [70]. These reactions ranged from a mild rash that resolved with continued drug administration to more severe reactions consisting of a diffuse rash accompanied by constitutional symptoms, including fever and hypotension, leading to discontinuation of the drug [71-73]. There has been a single case report of anaphylactoid reaction after a single oral dose of probenecid [74].

Sulphadoxine-pyrimethamine (SP)

Despite a long list of potentially severe side effects associated with sulphonamides, the dose of SP used for IPTp is generally well tolerated [50,51]. Bone marrow suppression including agranulocytosis, aplastic anaemia, megaloblastic anaemia, thrombocytopenia, leukopenia, haemolytic anaemia, and eosinophilia may be seen. Haematologic adverse events are related to folic acid antagonism, and can generally be reversed with folinic acid [51]. Mild adverse reactions, such as nausea, vomiting, rash, pruritus, and fatigue have been reported in a small proportion (1-2%) of patients following a single dose of SP [1,75-77]. Parise et al. reported an increased incidence of adverse events in women with HIV, but this was not confirmed in a study by Filler et al. [75,76]. Severe adverse events are rare [1]. Cutaneous hypersensitivity reactions (i.e. Stevens-Johnson syndrome and toxic epidermal necrolysis) are the most common severe adverse events. In studies of travellers taking weekly SP for malaria prophylaxis, the rate of cutaneous hypersensitivity reactions has been reported to be approximately one per 5,000-8,000, with one fatality per 11,000-25,000 [78-80]. The crude rate of cutaneous hypersensitivity reaction was reported to be approximately 1.2 per 100,000 exposures to SP in passive surveillance data from 22 health facilities in Blantyre, Malawi [81]. In that study, the rate of cutaneous hypersensitivity in HIV-infected individuals was approximately four times the crude rate, at 4.9 cases per 100,000 [81]. In a study comparing IPTp with standard SP to SP plus azithromycin, Luntamo et al. reported 14 maternal severe adverse events, including one maternal death, among 1,320 women (1%). However, the majority of these were considered to be unrelated to the study drugs [82]. It is unclear whether any of the reported adverse events were severe cutaneous reactions. In a systematic review of IPTp-SP, ter Kuile et al. report a total of 21 maternal deaths among 11,379 doses of SP given to 4,911 women; nine of these occurred in women receiving placebo [1]. Only one of these deaths was reported to be due to a severe cutaneous hypersensitivity reaction, and it occurred in an HIV-positive woman three weeks after the dose of SP [1,77]. A more comprehensive review of cutaneous hypersensitivity reactions was conducted by Peters et al. [51]. Other, less common, severe reactions that have been seen with SP use include liver toxicity (e.g. cholestatic hepatotoxicity and fulminant hepatic necrosis), fever, and respiratory problems such as hypersensitivity pneumonitis [51]. Patients with G6PD deficiency can safely receive SP-IPTp or malaria treatment with SP [51,83].


Probenecid is known to cross the placental barrier and appears in cord blood [48]. There are limited data on the use of probenecid in pregnancy, with approximately 460 cases described in the literature (Table 1). In most of these cases, no data are provided on the outcome of pregnancy. Of the few studies that describe foetal outcomes, none shows a statistically significant increase in foetal adverse events in infants exposed to probenecid compared to controls [84], although the small sample size of most of these studies is a major limitation to effectively evaluating infant outcomes. Due to the paucity of data, the US Food and Drug Administration classifies probenecid as Pregnancy Category B. However, the data available do not suggest any evidence of teratogenic effects of probenecid when used in pregnancy [48,55].


SP is classified by the US Food and Drug Administration as belonging to Pregnancy Category C. Pyrimethamine is teratogenic at doses well above the standard human dose in rats, hamsters and miniature pigs; effects including foetal re-absorption, cleft palate, bradygnathia, oligodactyly, and microphthalmia have been seen [50]. Sulphadoxine is also teratogenic in rats [50]. In rabbits, no teratogenic effects were noted at oral doses as high as 20 mg/kg pyrimethamine plus 400 mg/kg sulphadoxine [50]. One large study in humans looking at the effect of folic acid antagonists found an increased risk of malformations, including cardiovascular defects, oral clefts, and urinary tract defects, with exposure in the first trimester, but not in subsequent trimesters [91]. However, several large studies of SP-IPTp, including several randomized controlled trials, have not found an association between the use of SP and congenital anomalies [67,68]. Therefore, despite data suggesting teratogenicity in certain animal models, there is a large body of evidence suggesting that SP-IPTp is safe for use in humans during the second and third trimesters. Of note, probenecid in combination with SP would potentiate the antifolate effect of SP [36], with the potential danger of reducing the folates available to the growing foetus. Therefore, should this combination be adopted, careful monitoring is suggested to ensure that the combination does not have harmful effects [13].

Both pyrimethamine and sulphadoxine cross the placental barrier and also pass into breast milk [50]. Sulphonamides could theoretically increase the risk of kernicterus in the infant if given to a pregnant woman near term, due to the ability of sulphonamides to displace unconjugated bilirubin from albumin [51]. However, this has not actually been seen in clinical trials of IPTp, clinical treatment of cases of malaria or in the treatment of congenital toxoplasmosis (which uses pyrimethamine, sulphadiazine and folinic acid) [51,91].

Drug interactions

Probenecid is a ucosuric agent that inhibits the tubular secretion of organic anion derivatives. These organic anions (such penicillin and analogs), which are primarily derivatives of carboxylic acid (DCA), are secreted in the kidney by organic anion transporters (OATs). Probeneicd, which is also a DCA, interacts with these OATs, leading to a decrease in DCA secretion [92,93]. Thus, the mechanism of action of probenecid depends on the inhibition of OATs, reducing the secretion of DCA. Most of the drugs reported in the list below are organic anion compounds that are secreted through OATs, hence their interaction with probenecid. In the next section, we detail specific probenecid-drug interaction.

List of drugs whose concentration or effects are increased by probenecid

Antibacterials: Penicillins, Cephalosporins, Carbapenems, Quinolones, Dapsone, Rifampin, Tazobactam

Antivirals: Ganciclovir, Valganciclovir, Oseltamavir, Peramavir

Antiretrovirals: Zalcitabine, Zidovudine

• Methotrexate

• Acetaminophen

Non-steroidal anti-inflammatory drugs: Indomethacin, Ketoprofen, Ketorolac, Naproxen, Zomepirac

Benzodiazepines: Lorazepam, Midazolam, Nitrazepam

• Chlorothiazide (thiazide)

Loop Diuretics: Bumetanide, Furosemide

• Mycophenolate

Theophylline Derivatives: Dyphylline, Enprofylline but NOT Aminophylline or Theophylline

Sulphonylureas: Glimepiride, Glyburide

• Nitrofurantoin

• Apazone

• Entacapone

• Famotidine

• Pemetrexed

• Pralatrexate

• Sodium Phenylacetate, Sodium Benzoate

Probenecid is antagonized by both salicylates and pyrazinamide [31]. Allopurinol decreases the serum concentration of probenecid while probenecid increases that of allopurinol. However, the clinical significance of this is probably minimal [31]. Probenecid decreases the natriuretic effect of piretanide [31]. Probenecid increases the metabolism of phenprocoumon, leading to decreased AUC [94]. Probenecid has a nephroprotective effect when co-administered with cidofovir, but without significantly altering plasma blood levels [94]. It is a weak inhibitor of CYP2C19 and blocks the renal transport of many compounds including many classes of antibiotics, antivirals, and NSAIDs leading to an increase in their mean plasma elimination half-life that can lead to increased plasma concentrations [31]. In some cases, this may increase the potential for toxicity.


Neither sulphadoxine nor pyrimethine, nor their primary metabolites, are DCA [95,96], thus the mechanisms of secretion of these two drugs are not likely to involve OATs. Therefore, their pharmacokinetics would not be affected by probenecid. In support of this hypothesis, the clinical evaluation of probenecid with SP did not indicate any increase in sulfadoxine or pyrimethamine toxicity [19]. However, further investigations need to be carried out to establish the pharmacokinetics, safety, and efficacy of probenecid + SP, before this combination could be used routinely for IPTp.

SP should not be used in combination with other antifolates (i.e. trimethoprim), sulphonamides, or other agents associated with myelosuppression, as this can increase the risk of bone marrow suppression (Table 2). The concurrent use of gold salts and anti-malarial agents is also contraindicated due to an increased risk of blood dyscrasias. Sulphadoxine decreases the serum concentration of cyclosporine while enhancing its nephrotoxic effect. Potassium P-aminobenzoate and its derivatives (Procaine, benzocaine, and tetracaine) can decrease the therapeutic effect of sulphadoxine, while folate derivatives can decrease the therapeutic effect of pyrimethamine. The concomitant administration of antacids or absorbent anti-diarrhoeals may significantly reduce the bioavailability of pyrimethamine by reducing its absorption. Pyrimethamine inhibits CYP2C9 and CYP 2D6, and may therefore interact with other compounds, which are metabolized via these pathways (Table 3).

SP-IPTp works both through clearance of existing asymptomatic infections as well as prophylactically by preventing new infections [1]. The prophylactic effect of SP is believed to be of primary importance [1]. Due to the long half-life of SP, its parasitocidal drug levels are sustained for weeks in the case of sensitive parasites, providing a prolonged period of prophylaxis. As parasite resistance to SP increases, the period of prophylactic efficacy becomes shorter [21]. Even if probenecid can increase the concentration of SP, given the very short half-life of probenecid (less than 20 h) compared to SP (approximately 100 h), this effect is unlikely to be sustained. Therefore, while the addition of a single dose of probenecid to SP may be useful for treatment, it is unclear to what extent it will provide a prolonged period of prophylaxis in the context of IPTp. Multiple doses of probenecid may be needed to provide a sustained benefit of SP-IPTp. However, a multiple-dose regimen would be less ideal as compliance with such a regimen is likely to be low.


The antifolate SP is widely used for IPTp; it is the only drug currently recommended for IPTp by WHO and has been adopted as national policy in 37 countries worldwide, 33 of which are in the sub-Saharan region [97,98]. However, resistance of malaria parasites to SP has been increasing, and there is accumulating evidence from eastern Africa that the efficacy of SP-IPTp is declining. Therefore, new drugs and strategies are urgently needed. As malaria transmission declines, the risk associated with administering a drug to all pregnant women will no longer outweigh the potential benefit associated with preventing malaria, and it is likely that IPTp will be abandoned. In the interim, in vitro and in vivo data suggest that combining probenecid with SP significantly increases the efficacy of SP, and might therefore be a useful strategy in HIV-uninfected women until new drugs for IPTp are evaluated and deployed [13-16], although this combination may not be sufficiently efficacious in areas with a high degree of resistance. Although probenecid has been in use for many decades, very few data exist on its use in pregnancy; however, the available data suggests that it is safe. Prior to recommending this combination for widespread use, additional information is needed on its safety and pharmacokinetics in pregnancy, and given the difference in the half-lives of SP and probenecid, data are needed to determine the optimal dosing schedule. In addition, studies are needed to determine whether the increased dose of SP achieved by this combination improves the efficacy against partially resistant parasites. Mathematical modelling may be able to assist in this determination. Overall, available data on efficacy, safety and cost for these drugs necessitates further research into their combination for use in IPTp [48,55].


SP: Sulphadoxine-pyrimethamine; IPTp: Intermittent preventive treatment in pregnancy; dhps: Dihydropteroate synthetase; dhfr: Dihydrofolate reductase; G6PD: Glucose-6-phosphatase dehydrogenase; MRP: Multidrug resistance-associated protein; AUC: Area under the curve; OAT: Organic anion transporter; DCA: Derivatives of carboxylic acid

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

TK and AN were responsible for the concept of the manuscript. JG was responsible for the acquisition of data, interpretation of the data and writing the manuscript. SPK, LS, AN, and TK contributed to interpretation of the data and critically revised the paper. All authors have seen and approved the final version.


JG was supported in part by PHS Grant UL1 RR025008 and KL2 rR025009 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources and in part by the Malaria in Pregnancy Consortium (MiP), which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine. AN is grateful to King Fahd University of Petroleum and Minerals (KFUPM) for support.


The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

ter Kuile FO,van Eijk AM,Filler SJ,Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancyJAMAYear: 20072972603261610.1001/jama.297.23.260317579229
Aponte JJ,Schellenberg D,Egan A,Breckenridge A,Carneiro I,Critchley J,Danquah I,Dodoo A,Kobbe R,Lell B,May J,Premji Z,Sanz S,Sevene E,Soulaymani-Becheikh R,Winstanley P,Adjei S,Anemana S,Chandramohan D,Issifou S,Mockenhaupt F,Owusu-Agyei S,Greenwood B,Grobusch MP,Kremsner PG,Macete E,Mshinda H,Newman RD,Slutsker L,Tanner M,et al. Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trialsLancetYear: 20093741533154210.1016/S0140-6736(09)61258-719765816
Dicko A,Sagara I,Sissoko M,Guindo O,Diallo A,Kone M,Toure O,Sacko M,Doumbo O,Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in MaliMalar JYear: 2008712310.1186/1475-2875-7-12318611271
Thwing J,Eisele TP,Steketee RW,Protective efficacy of malaria case management and intermittent preventive treatment for preventing malaria mortality in children: a systematic review for the Lives Saved ToolBMC Publ HealthYear: 201111Suppl 3S1410.1186/1471-2458-11-S3-S14
Wilson A,IPTc TaskforceA systematic review and meta-analysis of the efficacy and safety of intermittent preventive treatment of malaria in children (IPTc)PLoS OneYear: 20116e1697610.1371/journal.pone.001697621340029
Greenwood B,Review: Intermittent preventive treatment--a new approach to the prevention of malaria in children in areas with seasonal malaria transmissionTrop Med Int HealthYear: 2006119839110.1111/j.1365-3156.2006.01657.x16827699
Gosling RD,Carneiro I,Chandramohan D,Intermittent preventive treatment of malaria in infants: how does it work and where will it work?Trop Med Int HealthYear: 2009141003101010.1111/j.1365-3156.2009.02303.x19558374
Maiga OM,Kayentao K,Traoré BT,Djimde A,Traoré B,Diallo M,Ongoiba A,Doumtabé D,Doumbo S,Traoré MS,Dara A,Guindo O,Karim DM,Coulibaly S,Bougoudogo F,Ter Kuile FO,Danis M,Doumbo OK,Superiority of 3 over 2 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria during pregnancy in Mali: a randomized controlled trialClin Infect DisYear: 20115321522310.1093/cid/cir37421765069
World Health OrganizationSusceptibility of Plasmodium falciparum to antimalarial drugs: Report on global monitoring: 1996-2004Technical document WHO/HTM/MAL/20051103 Geneva: World Health OrganizationYear: 2005
Gesase S,Gosling RD,Hashim R,Ord R,Naidoo I,Madebe R,Mosha JF,Joho A,Mandia V,Mrema H,Mapunda E,Savael Z,Lemnge M,Mosha FW,Greenwood B,Roper C,Chandramohan D,High resistance of Plasmodium falciparu to sulphadoxine/pyrimethamine in Northern Tanzania and the emergence of dhps resistance mutation at codon 581PLoS OneYear: 20094e456910.1371/journal.pone.000456919238219
World Health OrganizationGuidelines for the treatment of malariaYear: 20102Geneva: WHO
Harrington WE,Mutabingwa TK,Muehlenbachs A,Sorensen B,Bolla MC,Fried M,Duffy PE,Competitive facilitation of drug-resistant Plasmodium falciparu malaria parasites in pregnant women who receive preventive treatmentProc Natl Acad Sci USAYear: 20091069027903210.1073/pnas.090141510619451638
Harrington WE,Mutabingwa TK,Kabyemela E,Fried M,Duffy PE,Intermittent Treatment to prevent pregnancy malaria does not confer benefit in an area of widespread drug resistanceClin Infect DisYear: 20115322423010.1093/cid/cir37621765070
Feng G,Simpson JA,Chaluluka E,Molyneux ME,Rogerson SJ,Decreasing burden of malaria in pregnancy in Malawian women and its relationship to use of intermittent preventive therapy or bed netsPLoS OneYear: 20105e1201210.1371/journal.pone.001201220700457
Gosling RD,Cairns ME,Chico RM,Chandramohan D,Intermittent preventive treatment against malaria: an updateExpert Rev Anti Infect TherYear: 2010858960610.1586/eri.10.3620455687
Nzila AM,Kokwaro G,Winstanley PA,Marsh K,Ward SA,Therapeutic potential of folate uptake inhibition in Plasmodium falciparuTrends ParasitolYear: 20042010911210.1016/
Nzila A,Mberu E,Bray P,Kokwaro G,Winstanley P,Marsh K,Ward S,Chemosensitization of Plasmodium falciparu by Probenecid In VitroAntimicrob Agents ChemotherYear: 2003472108211210.1128/AAC.47.7.2108-2112.200312821454
Sowunmi A,Adedeji AA,Fateye BA,Fehintola FA,Comparative effects of pyrimethamine-sulfadoxine, with and without probenecid, on Plasmodium falciparu gametocytes in children with acute, uncomplicated malariaAnn Trop Med ParasitolYear: 20049887387810.1179/000349804X324315667719
Sowunmi A,Fehintola FA,Adedeji AA,Gbotosho GO,Falade CO,Tambo E,Fateye BA,Happi TC,Oduola AMJ,Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in childrenTrop Med Int HealthYear: 2004960661410.1111/j.1365-3156.2004.01233.x15117306
Mita T,Tanabe K,Kita K,Spread and evolution of Plasmodium falciparu drug resistanceParasitol IntYear: 20095820120910.1016/j.parint.2009.04.00419393762
White NJ,Intermittent Presumptive Treatment for MalariaPLoS MedYear: 20052e310.1371/journal.pmed.002000315696210
Kublin J,Dzinjalamala F,Kamwendo D,Malkin E,Cortese J,Martino L,Mukadam R,Rogerson S,Lescano A,Molyneux M,Winstanley PA,Chimpeni P,Taylor TE,Plowe CV,Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparu malariaJ Infect DisYear: 200218538038810.1086/33856611807721
Gregson A,Plowe CV,Mechanisms of resistance of malaria parasites to antifolatesPharmacol RevYear: 20055711714510.1124/pr.57.1.415734729
Watkins WM,Mberu EK,Winstanley PA,Plowe CV,The efficacy of antifolate antimalarial combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analysesParasitol TodayYear: 19971345946410.1016/S0169-4758(97)01124-115275132
Nyunt MM,Adam I,Kayentao K,van Dijk J,Thuma P,Mauff K,Little F,Cassam Y,Guirou E,Traore B,Doumbo O,Sullivan D,Smith P,Barnes KI,Pharmacokinetics of sulfadoxine and pyrimethamine in intermittent preventive treatment of malaria in pregnancyClin Pharmacol TherYear: 20098722623419776738
Boger WP,Strickland SC,PROBENECID (BENEMID) Its Uses and Side-Effects in 2,502 PatientsAMA Arch Intern MedYear: 195595839210.1001/archinte.1955.0025007009901213217507
Cunningham R,Israili ZH,Dayton PG,Clinical pharmacokinetics of probenecidClin PharmacokinetYear: 1981613515110.2165/00003088-198106020-000047011657
Holodniy M,Penzak SR,Straight TM,Davey RT,Lee KK,Goetz MB,Raisch DW,Cunningham F,Lin ET,Olivo N,et al. Pharmacokinetics and tolerability of oseltamivir combined with probenecidAntimicrob Agents ChemotherYear: 2008523013302110.1128/AAC.00047-0818559644
Rayner CR,Chanu P,Gieschke R,Boak LM,Jonsson EN,Population pharmacokinetics of oseltamivir when coadministered with probenecidJ Clin PharmacolYear: 20084893594710.1177/009127000832031718524996
Wolf DL,Rodriguez CA,Mucci M,Ingrosso A,Duncan BA,Nickens DJ,Pharmacokinetics and renal effects of cidofovir with a reduced dose of probenecid in HIV-infected patients with cytomegalovirus retinitisJ Clin PharmacolYear: 200343435110.1177/009127000223970512520627
Probenecid Oral Accessed March 9, 2011.
Roch-Ramel F,Renal transport of organic anionsCurr Opin Nephrol HypertensYear: 1998751752410.1097/00041552-199809000-000069818198
Kusuhara H,Sekine T,Utsunomiya-Tate N,Tsuda M,Kojima R,Cha SH,Sugiyama Y,Kanai Y,Endou H,Molecular cloning and characterization of a new multispecific organic anion transporter from rat brainJ Biol ChemYear: 1999274136751368010.1074/jbc.274.19.1367510224140
Sekine T,Watanabe N,Hosoyamada M,Kanai Y,Endou H,Expression cloning and characterization of a novel multispecific organic anion transporterJ Biol ChemYear: 1997272185261852910.1074/jbc.272.30.185269228014
Uwai Y,Okuda M,Takami K,Hashimoto Y,Inui K,Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidneyFEBS LettYear: 199843832132410.1016/S0014-5793(98)01328-39827570
Sirotnak FM,Wendel HG,Bornmann WGB,Tong WP,Miller VA,Scher HI,Kris MG,Co-administration of Probenecid, an inhibitor of a cMOAT/MRP- like plasma membrane ATPase, greatly enhanced the efficacy of a new 10-deazaaminopterin against human solid tumors in vivoClin Cancer ResYear: 200063705371210999764
Bertino JR,Goker E,Gorlick R,Li WW,Banerjee D,Resistance mechanisms to methotrexate in tumorsOncologistYear: 1996122322610387992
Watkins WM,Sixsmith DG,Chulay JD,Spencer HC,Antagonism of sulfadoxine and pyrimethamine antimalarial activity in vitro by p-aminobenzoic acid, p-aminobenzoylglutamic acid and folic acidMol Biochem ParasitolYear: 198514556110.1016/0166-6851(85)90105-73885030
Wang P,Sims PF,Hyde JE,A modified in vitro sulfadoxine susceptibility assay for Plasmodium falciparu suitable for investigating Fansidar resistanceParasitologyYear: 1997115Pt 32232309300459
Kinyanjui SM,Mberu EK,Winstanley PA,Jacobus DP,Watkins WM,The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitr activity against Plasmodium falciparu and a non- antifolate mode of action of the prodrugAmJTrop Med HygYear: 199960943947
van Hensbroek MB,Morris-Jones S,Meisner S,Jaffar S,Bayo L,Dackour R,Phillips C,Greenwood BM,Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malariaTrans R Soc Trop Med HygYear: 19958967267610.1016/0035-9203(95)90438-78594693
Kiara SM,Okombo J,Masseno V,Mwai L,Ochola I,Borrmann S,Nzila A,In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from Kenyan coast: Emergence of parasites with Ile-164-Leu mutationAntimicrob Agents ChemotherYear: 2009533793379810.1128/AAC.00308-0919528269
Sowunmi A,Adedeji AA,Fateye BA,Babalola CP,Plasmodium falciparum hyperparasitaemia in children. Risk factors, treatment outcomes, and gametocytaemia following treatmentParasiteYear: 20041131732315490757
Ilett KF,Hackett LP,Ingle B,Bretz PJ,Transfer of probenecid and cephalexin into breast milkAnn PharmacotherYear: 20064098698910.1345/aph.1G58016551765
Anderson R,Gambertoglio JG,Schrier RW,Clinical use of drugs in renal failureYear: 1976Springfield, Il: Charles C Thomas
Weber A,de Groot R,Ramsey B,Williams-Warren J,Smith A,Probenecid pharmacokinetics in cystic fibrosisDev Pharmacol TherYear: 1991167121879255
Selen A,Amidon GL,Welling PG,Pharmacokinetics of probenecid following oral doses to human volunteersJ Pharm SciYear: 1982711238124210.1002/jps.26007111147175716
Product Information: Benemid(R), probenecid tablets: Merck & CompanyYear: 1998West Point, PA
Bennett W,Aronoff GR,Golper TA,Morrison G,Singer I,Brater DC,Drug prescribing in renal failureYear: 1987Philadelphia: American College of Physicians
Fansidar Accessed March 9, 2011.
Peters PJ,Thigpen MC,Parise ME,Newman RD,Safety and toxicity of sulfadoxine/pyrimethamine: implications for malaria prevention in pregnancy using intermittent preventive treatmentDrug SafYear: 20073048150110.2165/00002018-200730060-0000317536875
Monograph - Pyrimethamine, Sulfadoxine and Pyrimethamine Accessed March 9, 2011.
Green MD,van Eijk AM,van ter Kuile FO,Ayisi JG,Parise ME,Kager PA,Nahlen BL,Steketee R,Nettey H,Pharmacokinetics of sulfadoxine-pyrimethamine in HIV-infected and uninfected pregnant women in Western KenyaJ Inf DisYear: 20071961403140810.1086/522632
Karunajeewa HA,Salman S,Mueller I,Baiwog F,Gomorrai S,Law I,Page-Sharp M,Rogerson S,Siba P,Ilett KF,Davis TM,Pharmacokinetic properties of sulfadoxine-pyrimethamine in pregnant womenAntimicrob Agents ChemotherYear: 2009534368437610.1128/AAC.00335-0919620325
Goodrich JT,Treatment of gonorrhea in pregnancySex Transm DisYear: 19796216817310.1097/00007435-197904000-00023158835
Swanson M,Cook R,Drugs, chemicals and blood dyscrasiasYear: 1977Hamilton, Il: Drug Intell Publications
Marks PA,Banks J,Drug induced hemolytic anemias associated with glucose-6-phosphate dehydrogenase deficiency: a genetically heterogenous traitAnn N Y Acad SciYear: 196512319820614329202
Chan T,Todd D,Tso SC,Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiencyBMJYear: 197621227122910.1136/bmj.2.6046.1227990860
Zail S,Charlton RW,Bothwell TH,The hemolytic effect of certain drugs in Bantu subjects with a deficiency of glucose 6 phosphate dehydrogenaseS Afr Med JYear: 1972279599
Cappellini MD,Fiorelli G,Glucose-6-phosphate dehydrogenase deficiencyLancetYear: 2008371647410.1016/S0140-6736(08)60073-218177777
Youngster I,Arcavi L,Schechmaster R,Akayzen Y,Popliski H,Shimonov J,Beig S,Berkovitch M,Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based reviewDrug SafYear: 20103371372610.2165/11536520-000000000-0000020701405
Sosler S,Behzad O,Garratty G,Lee CL,Postoway N,Khomo O,Immune hemolytic anemia associated with probenecidAm J Clin PatholYear: 1985843913944036870
Kickler T,Buck S,Ness P,Shirey RS,Sholar PW,Probenecid induced immune hemolytic anemiaJ RheumatolYear: 1986132082093701734
Ferris TF,Morgan WS,Levitin H,Nephrotic syndrome caused by probenecidNEJMYear: 196126538138310.1056/NEJM19610824265080713699173
Hertz P,Yager H,Richardson JA,Probenecid-induced nephritic syndromeArch PatholYear: 1972942412435051645
Izzedine H,Brocheriou I,Becart J,Deray G,Probenecid-induced membranous nephropathyNephrol Dial TransplantYear: 2007222405240617510101
Scott J,O'Brien PK,Probenecid, nephrotic syndrome, and renal failureAnn Rheum DisYear: 19682724925210.1136/ard.27.3.2495655316
Sokol A,Bashner MH,Okun R,Nephrotic syndrome caused by probenecidJAMAYear: 1967199434410.1001/jama.1967.031200100870266071127
Reynolds ES,Schlant RC,Gonick HC,Dammin GJ,Fatal massive necrosis of the liver as a manifestation of hypersensitivity to probenecidNEJMYear: 195725659259610.1056/NEJM19570328256130413451901
Myers K,Katial RK,Engler RJ,Probenecid Hypersensitivity in AIDS: a Case ReportAnn Allergy Asthma ImmunolYear: 19988041641810.1016/S1081-1206(10)62994-89609613
Lalezari JP,Drew WL,Glutzer E,James C,Miner D,Flaherty J,Fisher PE,Cundy K,Hannigan J,Martin JC,Jaffe HS,(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (Cidofovir): results of a phase i/ii study of a novel antiviral nucleotide analogueJ Inf DisYear: 199517178879610.1093/infdis/171.4.788
Petty B,Kornhauser D,Lietman P,Zidovudine with probenecid: a warningLancetYear: 1990335104410451970102
Polis MA,Spooner KM,Baird BF,Manischewitz JF,Jaffe HS,Fisher PE,Falloon J,Davey RT Jr,Kovacs JA,Walker RE,Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruriaAntimicrob Agents ChemotherYear: 1995398828867785989
Hillecke N,Acute anaphylactoid reaction to probenecidJAMAYear: 1965193116
Parise ME,Ayisi JG,Nahlen BL,Schultz LJ,Roberts JM,Misore A,Muga R,Oloo AJ,Steketee RW,Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infectionAm J Trop Med HygYear: 1998598138229840604
Filler SJ,Kazembe P,Thigpen M,Macheso A,Parise ME,Newman RD,Steketee RW,Hamel M,Randomized trial of 2-dose versus monthly sulfadoxine-pyrimethamine intermittent preventive treatment for malaria in HIV-positive and HIV-negative pregnant women in MalawiJ Infect DisYear: 200619428629310.1086/50508016826475
Hamer DH,Mwanakasale V,MacLeod WB,Chalwe V,Mukwamataba D,Champo D,Mwananyanda L,Chilengi R,Mubikayi L,Mulele CK,Mulenga M,Thea DM,Gill CJ,Two-dose versus monthly intermittent preventive treatment of malaria with sulfadoxine-pyrimethamine in hiv-seropositive pregnant Zambian WomenJ Infect DisYear: 2007196111585159410.1086/52214218008241
Miller KD,Lobel HO,Satriale RF,Kuritsky JN,Stern R,Campbell CC,Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (fansidar(r)) for malaria prophylaxisAm J Trop Med HygYear: 1986354514582939735
Hellgren U,Rombo L,Berg B,Carlson J,Wiholm BE,Adverse reactions to sulphadoxine-pyrimethamine in Swedish travellers: implications for prophylaxisBMJYear: 19872953653662958104
Phillips-Howard P,West LJ,Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in BritainJ R Soc MedYear: 19908382852138674
Gimnig JE,MacArthur JR,M'Bang'Ombe M,Kramer MH,Chizani N,Stern RS,Mkandala C,Newman RD,Steketee RW,Campbell CH,Severe cutaneous reactions to sulfadoxine-pyrimethamine and trimethoprim-sulfamethoxazole in Blantyre District, MalawiAm J Trop Med HygYear: 20067473874316687672
Luntamo M,Kulmala T,Mbewe B,Cheung YB,Maleta K,Ashorn P,Effect of Repeated treatment of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in Malawi: a randomized controlled trialAm J Trop Med HygYear: 2010831212122010.4269/ajtmh.2010.10-026421118924
Khoo K,The treatment of malaria in glucose-6-phosphate dehydrogenase deficient patients in SabahAnn Trop Med ParasitolYear: 1981755915957325735
Cavenee MR,Farris JR,Spalding TR,Barnes DL,Castaneda YS,Wendel GD Jr,Treatment of gonorrhea in pregnancyObstet GynecolYear: 19938133388416458
Adelson M,Graves WL,Osborne NG,Treatment of urinary infections in pregnancy using single versus 10-day dosingJ Natl Med AssocYear: 19928473751602504
Brown C,Saffan BD,Howard CM,Preedy JR,The Renal clearance of endogenous estrogens in late pregnancyJ Clin InvestYear: 19644329530310.1172/JCI10491414164476
Lee FI,Loeffler FE,Gout and pregnancyJ Obstet Gynaecol Br EmpYear: 196269229930410.1111/j.1471-0528.1962.tb00046.x14463488
Weingold AB,Gout and PregnancyObstet GynecolYear: 196016330931313843594
Schackis RC,Hyperuricaemia and preeclampsia: is there a pathogenic link?Med HypothesesYear: 20046323924410.1016/j.mehy.2004.02.01815236782
Czaczkes W,Ullmann TD,Sadowsky E,Plasma uric acid levels, uric acid excretion, and response to probenecid in toxemia of pregnancyJ Lab Clin MedYear: 19585122422913514228
Hernandez-Diaz S,Werler MM,Walker AM,Mitchell AA,Folic acid antagonists during pregnancy and the risk of birth defectsNEJMYear: 20003431608161410.1056/NEJM20001130343220411096168
Sweet D,Organic anion transporter (Slc22a) family members as mediators of toxicityToxicol Appl PharmacolYear: 200520419821510.1016/j.taap.2004.10.01615845414
Anzai N,Kanai Y,Endou H,Organic anion transporter family: current knowledgeJ Pharmacol SciYear: 200610041142610.1254/jphs.CRJ06006X16799257
Cundy KC,Petty BG,Flaherty J,Fisher PE,Polis MA,Wachsman M,Lietman PS,Lalezari JP,Hitchcock MJ,Jaffe HS,Clinical pharmacokinetics of cidofovir in human immunodeficiency virus- infected patientsAntimicrob Agents ChemotherYear: 199539124712527574510
Coleman M,Edwards G,Mihaly GW,Howells RE,Breckenridge AM,High-performance liquid chromatographic method for the determination of pyrimethamine and its 3-N-oxide metabolite in biological fluidsJ ChromatogrYear: 19843083633696746829
Dua V,Gupta NC,Sethi P,Edwards G,Dash AP,High-performance liquid chromatographic assay for the determination of sulfadoxine and N-acetyl sulfadoxine in plasma from patients infected with sensitive and resistant Plasmodium falciparu malariaJ Chromatogr B Analyt Technol Biomed Life SciYear: 200786016016510.1016/j.jchromb.2007.10.01617997367
World Health OrganizationWorld Malaria Report 2009Year: 2009Geneva: World Health Organization
World Health Organization. Malaria in Pregnancy Working GroupMinutes of the 8th Strategic Planning MeetingYear: 2007Geneva: World Health Organization


[Figure ID: F1]
Figure 1 

Hypothetical parasite burden profiles during pregnancy with SP IPT in a high-transmission setting. Entomological inoculation rate is about 50 infectious bites per person per year. Note that many infections self-cure (each infection is depicted as a green line). The hatched bars represent the duration of "suppressive prophylactic activity", and the solid bars represent the period during which parasite multiplication is suppressed (i.e. levels exceed the in vivo MIC). The horizontal dotted line at 108 parasites represents the level at which malaria can be detected on a blood film. (A) represents a drug-sensitive area; (B) represents a moderately resistant area. Reproduced from: White NJ (2005) Intermittent Presumptive Treatment for Malaria. PLoS Med 2(1): e3. doi:10.1371/journal.pmed.0020003

[TableWrap ID: T1] Table 1 

Reports of probenecid use during pregnancy

Author Study N Treatment Timing of Treatment SAEs Infant Outcome
Cavenee et al. [84] Treatment of gonorrhoea in pregnancy 123 Amoxicillin 3 gm + probenecid 1 gm 64 patients (25%) treated in 1st trimester of pregnancy None, one woman reported vomiting several hours after taking the drug 71 infants were evaluated, 14 treated < 14 week, 1 major malformation (7%), 4 minor malformations (29%); 57 > 14 week, 0 major and 10 minor malformations (18%), overall 1% major and 20% minor malformations, not statistically different from other groups

Adelson et al. [85] Treatment of urinary tract infections in pregnancy 98 Ampicillin 3.5 gm + probenecid 1 gm Not stated 3 patients developed candidal vulvo-vaginitis, 3 patients developed diarrhoea Not stated

Brown et al. [86] Renal clearance of oestrogen in pregnancy 9 Probenecid 2.5 gm Last 6 weeks of pregnancy None reported No foetal deaths or stillbirths

Lee et al. [87] Gout and pregnancy 1 Probenecid 1 gm to 3 gm daily throughout pregnancy Throughout pregnancy Anaemia thought related to renal disease Healthy infant

Weingold et al. [88] Gout and pregnancy 1 Colchicine and probenecid Throughout 1st pregnancy and for the first 14 weeks of 2nd pregnancy Mild anaemia 1st pregnancy: infant died on DOL4 due to hyaline membrane disease
2nd pregnancy: healthy infant

Goodrich [55] Gonorrhoea and pregnancy 163 Penicillin G 4.8 × 106 U (n = 158) or ampicillin (n = 5) + probenecid 1 gm Not stated None reported Not stated

Schackis [89] Hype-ruricemia and pre-eclampsia 20* Probenecid 250 mg twice daily for 7 days 26-32 weeks gestation No side-effects to probenecid were recorded There were 3 intrauterine foetal deaths: 1 from an abruptio placenta (> 1 kg) in the probenecid group and 2 from suspected placental insufficiency (both < 1 kg): 1 each in the probenecid and placebo group.

Czaczkes et al. [90] Pre-eclampsia, eclampsia 18† Probenecid 0.5 gm 3 times daily for 5-6 days Not stated None reported Not stated

*20 women treated and an additional 20 untreated controls

†15 women with pre-eclampsia + 3 pregnant controls without pre-eclampsia

[TableWrap ID: T2] Table 2 

Drugs that interact with sulphadoxine

Drug Effect of Interaction
Phenytoin Serum hydantoin levels and risk of toxicity may be increased due to inhibition of hepatic metabolism by sulphadoxine

Sulphonylureas (Glimepiride, Glyburide) The hypoglycemic potential of the sulphonylureas may be increased; the mechanism of this interaction is unknown.

Vitamin K antagonists (Coumadin, anisindione) Co-administration with a sulphonamide may increase the plasma concentrations and hypoprothrombinemic effects of coumarin anticoagulants

Gold salts Increase the risk of blood dyscrasias

Cyclosporine Sulphadoxine decreases the serum concentration of cyclosporine while enhancing its nephrotoxic effect

[TableWrap ID: T3] Table 3 

Drugs that interact with pyrimethamine

Drug Effect of Interaction
Gold salts Increased risk of blood dyscrasias

Methotrexate Increased risk of bone marrow suppression

Dapsone Folate antagonists may increase the likelihood of adverse hematologic reactions (e.g., agranulocytosis, anaemia)

Carvedilol Possible for increased serum concentration of the S-carvedilol enantiomer

Phenothiazines Anti-malarial agents may increase the serum concentration

Fesoterodine Serum concentrations of the active metabolite may be increased

Nebivolol Serum concentration may be increased

Zidovudine, abacavir, lamivudine Increased risk of bone marrow suppression

Tamoxifen Metabolism of Tamoxifen to the active metabolites may be decreased

Lorazepam Increases risk of elevated liver function tests

Codeine CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine, diminishing its therapeutic effect

Tramadol CYP2D6 inhibitors may prevent the metabolic conversion to the active metabolite, diminishing its therapeutic effect

Antacids Reduce the absorption of pyrimethamine (decreased bioavailability)

Article Categories:
  • Review

Keywords: Malaria, Sulphadoxine-pyrimethamine, Probenecid, Pregnancy.

Previous Document:  Can a River Heal Itself? Natural Attenuation of Metal Contamination in River Sediment.
Next Document:  Thymic hyperplasia in a patient with Grave's disease.