A Comprehensive Clinical and Pharmacological Review of Sulfadoxine-Pyrimethamine

Section 1: Introduction and Pharmacological Profile

1.1. Overview and Drug Classification

Sulfadoxine-Pyrimethamine (SP) is a fixed-dose combination medication that has played a pivotal and evolving role in the global fight against malaria and other protozoal infections.[1] It is broadly classified as an anti-infective and antiprotozoal agent, with its primary application being the treatment and, more significantly in the modern era, the prevention of malaria caused by the parasite

Plasmodium falciparum.[2] The combination consists of two distinct active pharmaceutical ingredients, each with a specific mechanism of action that contributes to a potent synergistic effect.

The first component, Sulfadoxine, is a long-acting sulfonamide antibiotic.[1] As a member of the sulfonamide class, its primary pharmacological roles are as an antibacterial and antimalarial drug.[2] The United States Food and Drug Administration (FDA) formally categorizes sulfadoxine within the Established Pharmacologic Class [EPC] of Sulfonamides.[2] Its prolonged duration of action is a key feature that makes it suitable for intermittent preventive therapies.

The second component, Pyrimethamine, is an antiprotozoal agent belonging to the diaminopyrimidine class of drugs.[1] It functions as an antifolate compound, with a structure and mechanism of action similar to that of another antimalarial, proguanil.[3] Pyrimethamine is also indicated for the treatment of other parasitic diseases, including toxoplasmosis and cystoisosporiasis, often in combination with other agents.[6]

Together, these two components form a powerful therapeutic agent, which has been marketed globally under various brand names, most notably Fansidar.[1] The combination's place in clinical practice has shifted over decades, moving from a first-line treatment for drug-resistant malaria to a cornerstone of modern public health strategies for malaria prevention in highly vulnerable populations.

1.2. Chemical Composition and Properties

The distinct chemical structures of sulfadoxine and pyrimethamine are fundamental to their individual mechanisms of action and their ability to function synergistically.

Sulfadoxine is a complex sulfonamide derivative.

• Chemical Formula: Its molecular formula is $C_{12}H_{14}N_4O_4S$.[4]
• Chemical Structure: Structurally, sulfadoxine is defined as N'-(5,6-dimethoxypyrimidin-4-yl)sulfanilamide. It consists of a pyrimidine ring that is substituted with methoxy groups ($-OCH_3$) at the 5- and 6-positions. This substituted pyrimidine ring is linked via a sulfonamide bridge ($-SO_2NH-$) to a 4-aminobenzene group (a sulfanilamide moiety).[2] This specific chemical architecture allows it to act as a structural analog of para-aminobenzoic acid (PABA), a key substrate in the parasite's folate synthesis pathway.

Pyrimethamine is a diaminopyrimidine derivative with a distinct chlorophenyl group.

• Chemical Formula: Its molecular formula is $C_{12}H_{13}ClN_4$.[6]
• Chemical Name: The systematic chemical name for pyrimethamine is 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine.[7]
• Molecular Weight: It has a molecular weight of approximately 248.71 g/mol.[6]
• Chemical Structure: The core of the molecule is a pyrimidine ring substituted with two amino groups ($-NH_2$) at the 2- and 4-positions, making it a diaminopyrimidine. This ring is further substituted with an ethyl group ($-CH_2CH_3$) at the 6-position and, critically, a para-chlorophenyl group (a benzene ring with a chlorine atom at the 4-position) at the 5-position. This structure is responsible for its high-affinity binding to the parasite's dihydrofolate reductase enzyme.

1.3. Historical Context and Brand Formulations

The development and deployment of Sulfadoxine-Pyrimethamine are deeply intertwined with the history of antimalarial drug resistance. Pyrimethamine was first discovered in 1952 by the Nobel Prize-winning scientist Gertrude Elion at Burroughs-Wellcome and was introduced for medical use in 1953.[6] The fixed-dose combination of Sulfadoxine-Pyrimethamine was subsequently developed and received approval for medical use in the United States in 1981.[1]

Its rise to prominence occurred during the 1980s and 1990s as a direct response to the global spread of chloroquine-resistant P. falciparum.[3] For many malaria-endemic countries, particularly in Africa, SP became the new first-line therapy, replacing the failing chloroquine and providing a much-needed, affordable, and effective treatment option.[12] However, the widespread use of SP for treatment inevitably led to the selection and spread of parasites resistant to SP itself. Consequently, its role as a primary treatment for acute malaria has significantly diminished in most regions, and it has been largely superseded by Artemisinin-based Combination Therapies (ACTs).[14]

Despite its waning utility for treatment, SP remains a vital tool in public health and is included on the World Health Organization's (WHO) List of Essential Medicines, reflecting its indispensable role in malaria prevention.[1] The standard oral tablet formulation combines 500 mg of sulfadoxine with 25 mg of pyrimethamine.[3] Recognizing the need for pediatric-friendly formulations for large-scale prevention campaigns, dispersible tablets have also been developed for use in Seasonal Malaria Chemoprevention (SMC) and Intermittent Preventive Treatment in infants (IPTi).[18]

1.4. Pharmacokinetics

The pharmacokinetic profile of Sulfadoxine-Pyrimethamine is defined by its slow absorption and exceptionally long elimination half-lives, characteristics that have profoundly shaped its clinical applications and its long-term viability.

• Absorption and Bioavailability: Following oral administration, both sulfadoxine and pyrimethamine are well absorbed from the gastrointestinal tract. Peak plasma concentrations (Tmax) for both components are typically reached approximately 2 to 6 hours after ingestion.[1]
• Distribution and Protein Binding: Both drugs exhibit extensive distribution throughout the body and are highly bound to plasma proteins. Approximately 87% of pyrimethamine and 90% of sulfadoxine are protein-bound, which contributes to their long duration of action.[1] Both components readily cross the placental barrier and are excreted into breast milk, a critical consideration for their use in pregnant and lactating women.[20] Furthermore, sulfadoxine is known to cross the blood-brain barrier, achieving concentrations in the cerebrospinal fluid that are 30% to 60% of those in the plasma.[16]
• Metabolism and Elimination: Both sulfadoxine and pyrimethamine are metabolized primarily in the liver.[6]
• Elimination Half-Life: The most distinguishing pharmacokinetic feature of SP is the remarkably long elimination half-life of its components.
• Pyrimethamine: The half-life is approximately 96 to 111 hours.[1]
• Sulfadoxine: The half-life is even longer, ranging from 169 to 184 hours (approximately 7 to 8 days).[1]

This pharmacokinetic profile can be viewed as a "double-edged sword" that has dictated the entire life cycle of SP as an antimalarial agent. The long half-lives are the very reason the drug is so effective for preventive strategies; a single dose can maintain protective drug concentrations in the blood for weeks, making it ideal for intermittent dosing in programs like IPTp and SMC.[14] This prolonged activity is its principal advantage. However, this same characteristic is also its greatest liability in the context of drug resistance. As the drugs are slowly eliminated, they create a long period of sub-therapeutic concentrations in the body. This extended window of low drug levels provides a powerful and sustained selective pressure on the parasite population, favoring the survival and proliferation of any parasites that happen to carry resistance-conferring mutations in the

pfdhfr and pfdhps genes.[13] Therefore, the very property that made SP an excellent prophylactic agent is also a direct driver of the evolutionary process that has led to its widespread resistance. This inherent contradiction explains why a once-critical treatment is now almost exclusively used for prevention, and why even that role is under constant threat from the parasite's relentless adaptation.

Pharmacokinetic Parameter	Pyrimethamine	Sulfadoxine
Time to Peak Plasma Concentration (Tmax)	2–6 hours	~4 hours
Plasma Protein Binding	~87%	~90%
Elimination Half-Life	96–111 hours	169–184 hours
Primary Route of Metabolism	Hepatic	Hepatic

Section 2: Mechanism of Action: Synergistic Folate Antagonism

The potent antimalarial activity of Sulfadoxine-Pyrimethamine stems from its elegantly designed mechanism of action, which exploits a fundamental biochemical vulnerability in the Plasmodium parasite. The two drugs work in concert to create a sequential and synergistic blockade of the parasite's folate synthesis pathway, a process essential for its survival and replication.

2.1. The Folate Synthesis Pathway in Plasmodium falciparum

Folic acid, in its biologically active form of tetrahydrofolate, is an indispensable cofactor for all living cells. It serves as a carrier of one-carbon units required for the synthesis of essential building blocks, including purines and pyrimidines (for DNA and RNA) and certain amino acids.[2] Without a steady supply of tetrahydrofolate, cells cannot replicate their genetic material or synthesize necessary proteins, leading to a halt in cell division and eventual death.

A critical divergence in metabolism exists between the human host and the malaria parasite, which forms the basis of SP's selective toxicity. Human cells are incapable of synthesizing folic acid de novo and must obtain it from their diet as a vitamin. This pre-formed folate is then taken up by cells through specialized transport mechanisms.[2] In stark contrast, the

Plasmodium parasite, like many bacteria and protozoa, cannot effectively transport and utilize exogenous folate from its host's bloodstream. It is therefore entirely dependent on its own machinery to synthesize folate from a simple precursor, para-aminobenzoic acid (PABA).[2] This metabolic distinction creates a perfect therapeutic window: a drug that targets the parasite's

de novo folate synthesis pathway can be highly toxic to the parasite while having minimal impact on the host, who relies on a different pathway for folate acquisition.

2.2. Sequential Enzymatic Blockade

Sulfadoxine-Pyrimethamine achieves its effect by inhibiting two separate and consecutive enzymatic steps within this vital parasite-specific pathway, a strategy known as sequential blockade.[1]

2.2.1. Sulfadoxine's Role: Inhibition of Dihydropteroate Synthetase (DHPS)

The first step in the parasite's folate synthesis pathway is the conversion of PABA into dihydropteroate. This reaction is catalyzed by the enzyme dihydropteroate synthetase (DHPS).[2] Sulfadoxine is a structural analog of PABA, meaning its chemical shape is very similar to that of the natural substrate.[21] Because of this similarity, sulfadoxine acts as a competitive inhibitor of DHPS. It binds to the active site of the enzyme, physically blocking PABA from entering and participating in the reaction.[21] This effectively shuts down the first stage of the pathway, preventing the formation of dihydropteroate and its subsequent conversion to dihydrofolic acid.

2.2.2. Pyrimethamine's Role: Inhibition of Dihydrofolate Reductase (DHFR)

The next critical step in the pathway is the reduction of dihydrofolic acid to the biologically active tetrahydrofolic acid. This conversion is catalyzed by the enzyme dihydrofolate reductase (DHFR).[5] Pyrimethamine is a potent and selective inhibitor of the parasite's DHFR enzyme.[1] Its molecular structure allows it to bind with very high affinity to the active site of plasmodial DHFR, much more tightly than it binds to the human version of the enzyme. This selectivity is a key feature that enhances its therapeutic efficacy while minimizing toxicity to the host.[5] By blocking DHFR, pyrimethamine prevents the final, essential step in the production of tetrahydrofolate, even if some dihydrofolic acid were to be produced despite the action of sulfadoxine.

2.3. The Synergistic Effect

The combination of these two drugs results in a "profound antimalarial synergy," where the combined effect is significantly greater than the simple sum of their individual effects.[3] This synergy arises from the dual, sequential nature of the blockade. By targeting two different points in the same linear pathway, the combination achieves a much more complete and robust inhibition of tetrahydrofolate synthesis than either agent could achieve on its own.[1] If a small amount of dihydrofolic acid bypasses the sulfadoxine-induced DHPS block, it is then caught by the pyrimethamine-induced DHFR block.

This synergistic mechanism is not merely about enhancing potency; it represents a foundational strategy in antimicrobial therapy designed to overcome the evolutionary inevitability of drug resistance. For a parasite to survive in the presence of SP, it would need to develop resistance to both drugs simultaneously. A mutation in the dhps gene might render sulfadoxine ineffective, but the parasite would still be susceptible to pyrimethamine's action on DHFR. Conversely, a mutation in the dhfr gene would be thwarted by sulfadoxine's continued inhibition of DHPS.[5] The statistical probability of a single parasite spontaneously acquiring effective resistance mutations in two different genes at the same time is exceedingly low. This multi-target approach was a forward-thinking design, an early example of the combination therapy principles that are now standard for treating complex infectious diseases like HIV, tuberculosis, and malaria itself with ACTs. The fact that widespread resistance to SP eventually did emerge after decades of intense drug pressure does not invalidate the soundness of the initial strategy; rather, it serves as a testament to the immense adaptive capacity of

P. falciparum.

Section 3: Clinical Indications and Therapeutic Applications

The clinical utility of Sulfadoxine-Pyrimethamine has undergone a significant transformation over its history, dictated largely by the evolving landscape of parasite resistance. Originally deployed as a primary weapon for treating acute malaria, its role has shifted almost entirely towards large-scale public health interventions for malaria prevention in the most vulnerable populations.

3.1. Treatment of Uncomplicated Plasmodium falciparum Malaria

Historically, SP was a cornerstone of malaria treatment, particularly following the global spread of chloroquine resistance.[2] It was adopted as the first-line therapy for uncomplicated

P. falciparum malaria in numerous endemic countries.[11] However, due to the relentless selective pressure from its widespread use, parasite resistance to SP became highly prevalent, leading to unacceptable rates of treatment failure.[14] As a result, its use as a monotherapy or as a primary treatment for acute malaria has been discontinued in most parts of the world.

Despite this, SP has not been entirely abandoned for treatment. The World Health Organization (WHO), in its November 2022 guidelines, continues to recommend Artesunate + Sulfadoxine-Pyrimethamine (AS+SP) as one of six acceptable Artemisinin-based Combination Therapies (ACTs) for uncomplicated P. falciparum malaria.[25] In this combination, the fast-acting artemisinin derivative (artesunate) provides rapid parasite clearance, while the long-acting SP component serves as a "partner drug" to eliminate the remaining parasites and provide a period of post-treatment prophylaxis. This combination strategy helps protect the artemisinin component from the development of resistance.

3.2. Malaria Chemoprevention Strategies

The exceptionally long half-lives of both sulfadoxine and pyrimethamine make the combination uniquely suited for intermittent preventive strategies, which now represent its most important clinical application.[14]

3.2.1. Intermittent Preventive Treatment in pregnancy (IPTp)

IPTp with SP is a cornerstone public health intervention recommended by the WHO for the control of malaria in pregnancy in regions of moderate-to-high transmission in Africa.[1] Malaria during pregnancy is a major cause of maternal and infant morbidity and mortality, leading to maternal anemia, stillbirth, and low birth weight (LBW), a primary risk factor for neonatal death.[14] The IPTp-SP strategy involves the administration of a full curative dose of SP to pregnant women at each scheduled antenatal care visit, beginning as early as possible in the second trimester.[14] Numerous studies have demonstrated the profound benefits of this intervention. A full course of IPTp-SP has been shown to decrease the incidence of low birth weight by 29%, severe maternal anemia by 38%, and neonatal mortality by 31%.[19] It remains one of the few health interventions proven to reduce neonatal mortality on a large scale.[19]

3.2.2. Seasonal Malaria Chemoprevention (SMC)

In the Sahel sub-region of Africa and other areas where malaria transmission is highly seasonal, the majority of cases occur within a few months of the year. For this epidemiological setting, the WHO strongly recommends Seasonal Malaria Chemoprevention (SMC).[22] This strategy involves the administration of monthly treatment courses of SP combined with amodiaquine (SP-AQ) to all children under a certain age (typically 3 to 59 months, though sometimes extended up to 10 years) during the high-transmission season.[14] SMC has proven to be a highly effective intervention, preventing over 75% of clinical malaria episodes and severe malaria in children who receive it.[14] By 2022, this program was being administered to nearly 49 million children per cycle across 17 countries, preventing millions of cases of malaria each year.[14]

3.2.3. Perennial Malaria Chemoprevention (PMC) / Intermittent Preventive Treatment in infants (IPTi)

For infants living in areas with year-round (perennial) malaria transmission, a similar strategy known as Perennial Malaria Chemoprevention (PMC), or Intermittent Preventive Treatment in infants (IPTi), is recommended. This involves giving intermittent doses of SP to infants, typically delivered through the existing Expanded Program on Immunization (EPI) platform during routine vaccination visits in the first year of life.[14] This approach has been shown to reduce the incidence of clinical malaria, severe malaria, and anemia in this highly vulnerable age group.[14]

The clinical journey of SP illustrates a critical paradigm shift in malaria control, from a reactive "firefighting" approach (treating active infections) to a proactive "fire prevention" strategy (chemoprevention). This evolution was not a deliberate strategic choice but rather a necessary adaptation forced by the parasite's evolution of resistance. The very resistance that caused SP to fail as a reliable cure for acute illness did not completely abrogate its ability to suppress parasite multiplication when administered prophylactically to specific populations, such as partially immune pregnant women or young children. This demonstrates a vital lesson in public health pharmacology: the clinical value of a drug is highly context-dependent. A drug that has "failed" in one setting (treatment of symptomatic individuals) can remain a life-saving, cornerstone intervention in another (prevention in high-risk groups), highlighting the need for nuanced, evidence-based policies that reposition, rather than completely discard, valuable therapeutic assets.

3.3. Other Protozoal Infections (Off-Label Use)

Beyond malaria, the antifolate activity of SP makes it effective against other protozoal pathogens that rely on de novo folate synthesis.

3.3.1. Toxoplasmosis (Toxoplasma gondii)

SP is active against Toxoplasma gondii, the parasite responsible for toxoplasmosis.[3] Pyrimethamine, combined with a sulfonamide (such as sulfadiazine or sulfadoxine), is considered a first-line regimen for the treatment of active toxoplasmosis, particularly toxoplasmic encephalitis, a severe and often life-threatening opportunistic infection in immunocompromised individuals, such as those with HIV/AIDS.[3]

3.3.2. Pneumocystis jiroveci Pneumonia (PJP)

SP has also been used as a second-line agent for the prophylaxis (prevention) of Pneumocystis jiroveci pneumonia (PJP), another critical opportunistic infection in immunocompromised patients.[1] The standard of care for PJP prophylaxis is trimethoprim-sulfamethoxazole (TMP-SMX). However, for patients who are unable to tolerate TMP-SMX, SP has been used as an alternative.[37] Its use for this indication is now rare, largely due to the significant risk of severe hypersensitivity reactions associated with long-term prophylactic dosing.[36]

Section 4: Dosage and Administration Guidelines

The administration of Sulfadoxine-Pyrimethamine requires precise dosing that varies significantly based on the clinical indication (treatment vs. prevention), the patient's age and weight, and specific public health guidelines. Adherence to these recommendations is critical for ensuring efficacy and minimizing the risk of adverse events.

4.1. Malaria Treatment

When used for the treatment of an acute malaria infection, SP is typically administered as a single oral dose. In many historical and current protocols, its administration follows a course of a more rapidly acting schizonticide, such as quinine, to quickly reduce the initial parasite burden.

• Adults: The standard adult dose is 2 to 3 tablets (equivalent to 1000–1500 mg sulfadoxine and 50–75 mg pyrimethamine), taken as a single dose.[16] This is often preceded by a 3 to 7-day course of quinine (e.g., 650 mg every 8 hours).[39]
• Pediatric Patients (>2 months of age): Dosing for children is based on body weight and is also administered as a single oral dose.[39]
• 5–10 kg: 0.5 tablet
• 11–20 kg: 1 tablet
• 21–30 kg: 1.5 tablets
• 31–45 kg: 2 tablets
• >45 kg: 3 tablets

4.2. Malaria Prophylaxis

While no longer routinely recommended for travelers due to the risk of severe adverse reactions, historical guidelines for malaria prophylaxis provide insight into its long-acting properties.[1]

• Adults: Two primary regimens were used: 1 tablet taken once weekly, or 2 tablets taken once every two weeks. The regimen was to be initiated 1 to 2 days before entering an endemic area and continued for the duration of the stay and for 4 to 6 weeks after returning.[16]
• Pediatric Patients (>2 months of age): A weekly, weight-based regimen was recommended.[39]
• 5–10 kg: 0.25 tablet weekly
• 11–20 kg: 0.5 tablet weekly
• 21–30 kg: 0.75 tablet weekly
• 31–45 kg: 1 tablet weekly
• >45 kg: 1.5 tablets weekly

4.3. Intermittent Preventive Treatment in pregnancy (IPTp-SP)

The dosing for IPTp-SP is standardized according to WHO guidelines to maximize its protective benefits for both mother and fetus.

• Dosage: A single treatment course consists of a standard dose of 3 tablets, providing a total of 1500 mg of sulfadoxine and 75 mg of pyrimethamine.[18]
• Timing and Frequency: According to WHO recommendations, IPTp-SP should be initiated as early as possible in the second trimester of pregnancy (it is contraindicated in the first trimester).[18] Doses should be administered at each scheduled antenatal care visit, ensuring an interval of at least one month between doses.[18] The public health goal is for each pregnant woman to receive a minimum of three doses during her pregnancy, as evidence clearly shows that three or more doses confer greater benefits—including higher mean birth weight and a lower incidence of LBW—compared to only two doses.[18]
• Administration: To ensure adherence, the WHO recommends that the full dose be administered as Directly Observed Therapy (DOT) by a healthcare worker during the antenatal visit.[30] The tablets should be swallowed whole with a generous amount of fluid and may be taken after a meal to minimize potential gastrointestinal discomfort.[39]

4.4. Seasonal Malaria Chemoprevention (SMC)

For SMC, SP is co-administered with amodiaquine (AQ) in age- and weight-appropriate doses, typically using co-packaged, child-friendly dispersible tablets. The regimen is given monthly for 3 to 5 consecutive months during the peak malaria transmission season.[22]

4.5. Special Populations and Other Indications

• Patients with Renal or Hepatic Impairment: Caution is advised when administering SP to patients with impaired kidney or liver function. Repeated prophylactic use is strictly contraindicated in individuals with severe renal or hepatic failure due to the risk of drug accumulation and toxicity.[1]
• Prophylaxis for Pneumocystis jiroveci Pneumonia (PJP): For this off-label use, a typical dose is 1 tablet taken either once or twice per week.[39]

The following table consolidates the dosing information into a clear, referenceable format for clinical and public health use.

Indication	Patient Population	Dosage	Frequency and Duration	Key Administration Notes
Treatment of Uncomplicated Malaria	Adults	2–3 tablets (1000–1500 mg SP)	Single dose	Often preceded by a 3–7 day course of quinine.
	Pediatrics (>2 months)	Weight-based: 5–10 kg (0.5 tab); 11–20 kg (1 tab); 21–30 kg (1.5 tab); 31–45 kg (2 tab); >45 kg (3 tab)	Single dose	Often preceded by a 3–7 day course of quinine.
Malaria Prophylaxis (Not routinely recommended)	Adults	1 tablet	Once weekly	Start 1–2 days before travel; continue for 4–6 weeks after return.
	Pediatrics (>2 months)	Weight-based: 5–10 kg (0.25 tab); 11–20 kg (0.5 tab); 21–30 kg (0.75 tab); 31–45 kg (1 tab); >45 kg (1.5 tab)	Once weekly	Start 1–2 days before travel; continue for 4–6 weeks after return.
Intermittent Preventive Treatment in pregnancy (IPTp)	Pregnant Women	3 tablets (1500 mg SP)	Single dose at each scheduled antenatal visit, at least 1 month apart.	Start in 2nd trimester. Minimum of 3 doses recommended. Administer as Directly Observed Therapy (DOT).
Seasonal Malaria Chemoprevention (SMC)	Children (e.g., 3–59 months)	Age/weight-based dosing of SP + Amodiaquine (AQ)	Monthly for 3–5 cycles	Administered during the high-transmission season. Use co-packaged dispersible tablets.
P. jiroveci Pneumonia (PJP) Prophylaxis	Adults	1 tablet	Once or twice weekly	Second-line therapy for patients intolerant to TMP-SMX.

Section 5: Safety Profile, Adverse Effects, and Contraindications

While Sulfadoxine-Pyrimethamine is a critical public health tool, its use is associated with a well-defined spectrum of adverse effects, ranging from common and mild disturbances to rare but severe and potentially fatal toxicities. A thorough understanding of this safety profile and its absolute contraindications is essential for its safe and effective use.

5.1. Common and Mild Adverse Reactions

The majority of adverse events associated with SP are mild, transient, and manageable. These most frequently include:

• Gastrointestinal Disturbances: Nausea, vomiting, abdominal pain, diarrhea, and a sensation of fullness are among the most commonly reported side effects.[1] Taking the medication with food can help mitigate these symptoms.
• Dermatologic Reactions: Mild skin manifestations such as a non-severe rash, itching (pruritus), and hives (urticaria) may occur.[1] A slight, reversible hair loss (alopecia) has also been noted.[1]
• Central Nervous System Effects: Headache and dizziness are frequently reported adverse events.[1]
• General Systemic Symptoms: Some individuals may experience generalized fatigue, low-grade fever, or weight loss.[1]

5.2. Severe and Potentially Fatal Adverse Reactions

The primary concern with SP therapy is the risk of rare but life-threatening idiosyncratic reactions.

5.2.1. Hypersensitivity and Severe Cutaneous Adverse Reactions (SCARs)

This is the most significant and feared toxicity associated with SP. The medication can trigger a spectrum of severe hypersensitivity reactions, most notably Stevens-Johnson Syndrome (SJS) and its more severe variant, Toxic Epidermal Necrolysis (TEN).[1]

• Clinical Presentation: SJS/TEN typically begins with non-specific, flu-like symptoms (fever, sore throat, fatigue, burning eyes) followed by the rapid onset of a painful, widespread red or purple rash that blisters.[46] The top layer of the affected skin then dies and sheds, leaving raw, exposed areas susceptible to infection and fluid loss.
• Clinical Imperative: These conditions are medical emergencies requiring immediate hospitalization. It is critically important that SP be discontinued at the very first sign of any skin rash, no matter how mild, as this may be the initial manifestation of an impending SCAR.[42]
• Incidence: While rare, the risk is not negligible. The estimated incidence of fatal cutaneous reactions associated with SP use has been reported to be between 1 in 11,000 and 1 in 25,000 users.[45]

5.2.2. Hematologic Toxicity

As a folate antagonist, SP can interfere with human folic acid metabolism, particularly at high doses or with prolonged use, leading to bone marrow suppression (myelosuppression).[1]

• Manifestations: Severe hematologic adverse events have been reported, including megaloblastic anemia (due to impaired DNA synthesis in red blood cell precursors), aplastic anemia (complete bone marrow failure), agranulocytosis (a severe deficiency of granulocytes), leukopenia (low white blood cell count), and thrombocytopenia (low platelet count).[20] Fatalities resulting from these blood dyscrasias have occurred.[20]
• G6PD Deficiency: In individuals with a genetic deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), sulfonamides like sulfadoxine can induce acute hemolytic anemia.[20]

5.2.3. Hepatotoxicity

SP has been linked to rare cases of idiosyncratic, clinically significant liver injury.[3]

• Presentation: The liver injury often presents as part of a systemic drug-allergy or hypersensitivity reaction, characterized by the abrupt onset of fever, rash, and eosinophilia, followed by jaundice.[3]
• Pattern of Injury: The pattern of liver damage can be cholestatic (impaired bile flow) or mixed (both hepatocellular and cholestatic). In the most severe cases, it can progress to fulminant hepatic necrosis and acute liver failure.[3] Fortunately, most cases resolve rapidly upon discontinuation of the drug.[3]

5.2.4. Renal Toxicity

Adverse effects on the kidneys can occur, including acute interstitial nephritis, toxic nephrosis with oliguria or anuria, and crystalluria (the formation of drug crystals in the urine that can lead to obstruction).[43] Ensuring adequate patient hydration can help minimize the risk of crystalluria.[38]

The safety profile of SP is highly dependent on the specific dosing strategy employed. The risk-benefit calculation changes dramatically when comparing long-term, continuous prophylaxis with intermittent, therapeutic dosing. The severe and fatal cutaneous reactions like SJS/TEN were a primary driver in the decision to abandon routine weekly SP prophylaxis for travelers.[1] Continuous, prolonged exposure to the drug and its metabolites appears to increase the likelihood of triggering the idiosyncratic immune response that leads to these devastating reactions. In contrast, the extensive clinical data from IPTp and SMC programs, which utilize intermittent full therapeutic doses (e.g., one dose per month), consistently report a favorable safety profile and good tolerability.[18] This suggests that the risk of sensitization and severe reactions may be lower with intermittent dosing, which allows the system to clear the drug between exposures. This distinction underscores a critical principle in public health: drug safety is not a static property. A regimen deemed unacceptably risky for one indication (long-term prophylaxis) can be acceptably safe and life-saving for another (intermittent prevention in high-burden settings), where the benefit of preventing a deadly disease is immense.

5.3. Contraindications

There are several absolute contraindications to the use of Sulfadoxine-Pyrimethamine, designed to protect patients at the highest risk of severe adverse events.

• Hypersensitivity: A history of a significant allergic reaction to pyrimethamine, sulfadoxine, or any other sulfonamide ("sulfa") drug is an absolute contraindication.[1]
• Pre-existing Medical Conditions:
• Megaloblastic Anemia: Documented megaloblastic anemia resulting from folate deficiency is a contraindication, as SP would exacerbate the condition.[1]
• Severe Organ Dysfunction: Severe renal or hepatic failure is a contraindication for repeated or prophylactic use.[1]
• Blood Dyscrasias: Pre-existing severe blood disorders are a contraindication.[1]
• Specific Populations:
• Pregnancy: SP is contraindicated during the first trimester of pregnancy due to its antifolate mechanism and the theoretical risk of neural tube defects.[18] It is also contraindicated at term (in late pregnancy) due to the risk of displacing bilirubin from albumin in the newborn, potentially leading to kernicterus.[1]
• Lactation: SP is contraindicated during breastfeeding. Both drugs are excreted in breast milk and can pose risks to the nursing infant, particularly newborns and premature infants.[20]
• Infants: The drug is contraindicated in infants younger than 2 months of age due to the immaturity of their metabolic enzyme systems and the increased risk of kernicterus.[1]
• Concurrent Medication: SP is contraindicated in HIV-infected pregnant women who are receiving daily co-trimoxazole (TMP-SMX) prophylaxis, due to the overlapping mechanisms and increased risk of severe adverse reactions.[18]

5.4. Long-Term Effects

Long-term prophylactic use of SP, defined as continuous use for more than two years, is generally not recommended.[39] The primary long-term health effects associated with SP are typically the sequelae of severe acute adverse events. For survivors of SJS/TEN, this can include permanent skin damage such as scarring, changes in pigmentation (hypo- or hyperpigmentation), and chronic, debilitating eye problems like severe dry eye, light sensitivity, and, in some cases, visual impairment or blindness.[46] For patients on long-term therapy (e.g., for PJP prophylaxis), regular monitoring of complete blood counts, liver function tests, and renal function is essential to detect early signs of cumulative toxicity.[20]

Section 6: Drug and Disease Interactions

The clinical use of Sulfadoxine-Pyrimethamine can be complicated by a number of significant interactions with other drugs, dietary supplements, and underlying disease states. These interactions can alter the efficacy of SP or the co-administered drug, or increase the risk of toxicity. A comprehensive assessment of a patient's concurrent medications and medical history is therefore crucial before initiating therapy.

6.1. Pharmacodynamic Interactions

Pharmacodynamic interactions occur when two drugs have additive, synergistic, or antagonistic effects on the body.

• Other Folate Antagonists: This is one of the most clinically important interactions. When SP is co-administered with other drugs that inhibit the folate pathway or have myelosuppressive properties, the risk of bone marrow suppression is significantly increased. This includes medications such as:
• Trimethoprim (commonly found in co-trimoxazole, or TMP-SMX)
• Methotrexate (an anticancer and immunosuppressive agent)
• Proguanil (another antimalarial) The combined effect can lead to a higher incidence and severity of anemia, leukopenia, and thrombocytopenia.30 Concurrent use of SP and TMP-SMX is particularly hazardous, as it has been associated with an increased risk of severe cutaneous reactions, and is therefore contraindicated in populations such as HIV-positive pregnant women on co-trimoxazole prophylaxis.18
• Folic Acid Supplementation: The interaction with folic acid is complex and dose-dependent, representing a critical management issue, especially in pregnancy.
• High-Dose Folic Acid (≥5 mg/day): High doses of supplemental folic acid can directly antagonize the antimalarial efficacy of SP. By providing an exogenous source of folate, it allows the parasite to bypass the enzymatic blockade created by sulfadoxine and pyrimethamine, potentially leading to treatment or prophylactic failure.[10]
• Low-Dose Folic Acid (0.4 mg/day): In contrast, the standard low dose of folic acid recommended for all pregnant women to prevent neural tube defects does not appear to significantly interfere with the efficacy of SP.[10] This allows for the concurrent administration of these two essential interventions during pregnancy. However, some clinical guidelines recommend a precautionary measure of withholding the daily folic acid supplement for a period (e.g., two weeks) after each IPTp-SP dose to ensure maximum antimalarial effect, though this is not a universal practice.[18]

6.2. Pharmacokinetic Interactions

Pharmacokinetic interactions involve one drug affecting the absorption, distribution, metabolism, or excretion of another.

• Interactions Affecting SP Plasma Levels:
• Dihydroartemisinin-piperaquine (DP): Studies have shown that co-administration of DP, another antimalarial combination, with SP can lead to a clinically significant reduction in the plasma exposure of both sulfadoxine and pyrimethamine. Maximum concentrations (Cmax) and the area under the concentration-time curve (AUC) can be reduced by 25–34%. This interaction is of concern as it could potentially reduce the duration of the prophylactic effect of SP and compromise its efficacy in programs like IPTp.[56]
• Interactions Where SP Affects Other Drugs:
• Warfarin: Sulfonamides, including sulfadoxine, can potentiate the effect of oral anticoagulants like warfarin. They can displace warfarin from its binding sites on plasma albumin, increasing the concentration of free, active warfarin in the blood and thereby elevating the risk of bleeding.[49] Close monitoring of coagulation parameters (e.g., INR) is necessary if these drugs are used concurrently.
• Oral Hypoglycemic Agents: Sulfadoxine can enhance the glucose-lowering effect of sulfonylurea drugs (e.g., glipizide, glyburide). This occurs through displacement from protein binding sites and potential inhibition of metabolism, which increases the risk of hypoglycemia.[23]
• Phenytoin: As an anticonvulsant that also affects folate metabolism, phenytoin may have complex interactions with SP, potentially increasing the risk of folate deficiency and hematologic toxicity.[49]
• Cyclosporine: The combination of sulfadoxine and cyclosporine may increase the risk of nephrotoxicity.[23]

6.3. Disease Interactions

The safety and efficacy of SP can be altered by a patient's underlying health conditions. These interactions are closely related to the drug's contraindications.

• Renal and Hepatic Dysfunction: Impaired function of the kidneys or liver, the primary organs of drug elimination and metabolism, can lead to the accumulation of sulfadoxine and pyrimethamine. This increases the plasma concentrations and duration of exposure, heightening the risk of dose-related toxicities.[1]
• Folate Deficiency: In patients with pre-existing folate deficiency (e.g., due to malnutrition, alcoholism, or malabsorption), the administration of an antifolate drug like SP can precipitate or worsen megaloblastic anemia.[39]
• Hematologic Disorders: Patients with pre-existing blood dyscrasias are at higher risk of the myelosuppressive effects of SP.[20]
• Seizure Disorders: High doses of pyrimethamine have been associated with central nervous system toxicity and may lower the seizure threshold in susceptible individuals.[48]

The table below summarizes some of the most clinically important drug interactions.

Interacting Drug/Class	Severity	Mechanism of Interaction	Clinical Consequence	Management Recommendation
Trimethoprim/Sulfamethoxazole (TMP-SMX)	Major	Additive antifolate effect; overlapping toxicity profile	Increased risk of severe myelosuppression and severe cutaneous adverse reactions (SJS/TEN)	Avoid concurrent use. Contraindicated in specific populations (e.g., HIV+ pregnant women).
Methotrexate	Major	Additive antifolate effect	Increased risk of severe myelosuppression and pancytopenia	Avoid concurrent use unless absolutely necessary; requires intensive hematologic monitoring.
Folic Acid (High Dose, ≥5 mg/day)	Moderate	Pharmacodynamic antagonism	Reduced antimalarial efficacy of SP; potential for treatment/prophylactic failure	Avoid high-dose folic acid during SP therapy. Use standard low dose (0.4 mg/day) for pregnancy.
Warfarin	Moderate	Displacement from plasma protein binding	Increased anticoagulant effect; elevated risk of bleeding	Monitor INR closely and adjust warfarin dose as needed.
Sulfonylureas (e.g., Glipizide)	Moderate	Displacement from protein binding; potential metabolic inhibition	Increased hypoglycemic effect; risk of severe hypoglycemia	Monitor blood glucose levels closely; may require dose reduction of the sulfonylurea.
Dihydroartemisinin-piperaquine (DP)	Moderate	Pharmacokinetic interaction (mechanism unclear)	Reduced plasma concentrations of sulfadoxine and pyrimethamine; potentially reduced efficacy	Be aware of potential for reduced prophylactic cover. Further research is needed.

Section 7: Parasite Resistance and Public Health Implications

The greatest challenge to the sustained utility of Sulfadoxine-Pyrimethamine is the remarkable ability of the Plasmodium falciparum parasite to develop and spread drug resistance. This evolutionary battle has defined the clinical history of SP and continues to shape its future role in global malaria control. Understanding the molecular basis of this resistance and its clinical impact is paramount for effective public health policy.

7.1. Molecular Basis of Resistance

Resistance to SP is not an all-or-nothing phenomenon but rather a stepwise process involving the accumulation of specific point mutations (single-nucleotide polymorphisms or SNPs) in the parasite genes that encode the drug's target enzymes.[13]

• Pyrimethamine Resistance (pfdhfr gene): Resistance to pyrimethamine is conferred by mutations in the gene encoding the parasite's dihydrofolate reductase enzyme (pfdhfr). These mutations alter the amino acid sequence of the enzyme's active site, reducing the binding affinity of pyrimethamine. The key mutations occur at codons 51 (Asparagine to Isoleucine, N51I), 59 (Cysteine to Arginine, C59R), 108 (Serine to Asparagine, S108N), and 164 (Isoleucine to Leucine, I164L). The accumulation of these mutations, particularly the N51I+C59R+S108N "triple mutant," leads to high-level resistance.[13]
• Sulfadoxine Resistance (pfdhps gene): Similarly, resistance to sulfadoxine is caused by mutations in the gene for dihydropteroate synthetase (pfdhps), which reduce the drug's ability to competitively inhibit the enzyme. The most important mutations are found at codons 436 (Serine to Alanine, S436A), 437 (Alanine to Glycine, A437G), 540 (Lysine to Glutamate, K540E), 581 (Alanine to Glycine, A581G), and 613 (Alanine to Serine/Threonine, A613S/T). The A437G and K540E mutations are particularly significant markers of declining efficacy.[13]

The overall level of clinical resistance is strongly correlated with the total number of mutations present across both genes.[13]

7.2. Clinically Significant Resistance Haplotypes

In the field, specific combinations of these mutations, known as haplotypes, are used as molecular markers to track the spread of resistance and predict the clinical effectiveness of SP.

• The Quintuple Mutant: This highly resistant haplotype is defined by the presence of the pfdhfr triple mutant (N51I+C59R+S108N) combined with the pfdhps double mutant (A437G+K540E). The widespread prevalence of the quintuple mutant is strongly associated with the clinical failure of SP for treating acute malaria.[60] The pfdhps K540E mutation is often used as a key molecular proxy for this highly resistant genotype, as its presence typically signifies the full quintuple combination.[62]
• The Sextuple Mutant: An even more alarming development has been the emergence of "super-resistant" parasites. The sextuple mutant adds the pfdhps A581G mutation to the quintuple mutant background. The presence of this haplotype has been shown to severely compromise the effectiveness of IPTp-SP. In pregnant women infected with sextuple mutant parasites, SP fails to inhibit parasite growth, leading to higher placental parasite densities and a loss of the protective effect on birth weight.[14]

Gene	Key Mutations (Codon Change)	Associated Drug Resistance	Clinical Significance/Notes
pfdhfr	N51I, C59R, S108N	Pyrimethamine	The "triple mutant" combination confers high-level pyrimethamine resistance. A core component of clinically relevant resistance.
pfdhps	A437G, K540E	Sulfadoxine	The "double mutant" combination confers significant sulfadoxine resistance. The K540E mutation is a key marker for high-level resistance.
pfdhps	A581G	Sulfadoxine	When added to the quintuple mutant background, it creates the "sextuple mutant" or "super-resistant" parasite.
Quintuple Mutant Haplotype	pfdhfr I51+R59+N108 and pfdhps G437+E540	Pyrimethamine + Sulfadoxine	Associated with high rates of SP treatment failure for acute malaria. Reduces but does not eliminate the benefit of IPTp-SP.
Sextuple Mutant Haplotype	Quintuple Mutant + pfdhps G581	Pyrimethamine + Sulfadoxine	Associated with the failure of IPTp-SP to provide a protective benefit on birth weight. A critical threat to current prevention strategies.

7.3. Global and Regional Resistance Patterns

The emergence and spread of SP resistance followed a predictable geographical pattern, originating in epicenters of drug pressure in Southeast Asia and South America before being introduced to and spreading across Africa.[64] Today, the prevalence of resistance markers is high across most of sub-Saharan Africa, with particularly alarming levels in East and Southern Africa.[12]

• Recent surveillance in Central Africa (2016–2021) revealed a very high frequency of the pfdhfr triple mutant and concerning levels of pfdhps mutations, including the detection of super-resistant and even octuple mutants, signaling a deteriorating situation.[61]
• In contrast, data from Angola in 2019 showed that while some resistance markers were nearly fixed in the population, the prevalence of the key mutations that compromise IPTp efficacy (pfdhps K540E and A581G) remained below the critical thresholds defined by the WHO, suggesting that SP likely retains its effectiveness for prevention in that specific setting.[60] This highlights the importance of sub-national level surveillance, as resistance patterns can vary significantly even within a single region.

7.4. WHO Recommendations and Public Health Strategy

The widespread resistance to SP has created a complex public health dilemma, often referred to as the "SP paradox." Despite being largely ineffective for treating acute illness, SP remains the only WHO-recommended drug for the cornerstone prevention strategies of IPTp and SMC in Africa.[14]

• The Rationale for Continued Use: Extensive evidence shows that even in areas with a high prevalence of the quintuple mutant, IPTp-SP continues to provide a significant, albeit attenuated, public health benefit. It still reduces the incidence of low birth weight and maternal anemia.[14] The precise mechanisms for this retained efficacy are not fully understood but are thought to involve a combination of factors, including the clearance of drug-sensitive parasites, a general reduction in overall parasite burden, and a potential interaction with the unique acquired immunity of pregnant women.
• Monitoring Thresholds and Surveillance: In response to the growing threat, the WHO and its partners have established a strategy based on continuous molecular surveillance. Provisional thresholds have been set to guide policy: if the prevalence of the pfdhps A581G mutation rises above 10%, or the prevalence of the K540E mutation exceeds 95% in a given area, the efficacy of IPTp-SP is likely to be severely compromised, and alternative strategies must be considered.[27] This makes ongoing monitoring of these molecular markers an essential public health activity. Global collaborations like the WWARN SP Resistance Surveyor play a critical role in collating and mapping this data to inform national malaria control programs.[62]
• Future Directions: The continued spread of highly resistant parasites, especially the sextuple mutant, creates an urgent and pressing need to identify and develop effective, safe, and affordable alternative drugs to replace SP for malaria chemoprevention in the near future.[26]

Conclusion

Sulfadoxine-Pyrimethamine (SP) holds a unique and complex legacy in the history of global health. Born from the need for an effective therapy against chloroquine-resistant malaria, its elegant synergistic mechanism—a sequential blockade of the parasite's essential folate synthesis pathway—made it a vital tool for treatment for several decades. However, the very pharmacokinetic properties that contributed to its efficacy, namely its exceptionally long half-lives, also created the ideal conditions for the selection and spread of resistant Plasmodium falciparum parasites.

This evolutionary pressure has forced a profound shift in the drug's clinical role. While now largely obsolete for the treatment of acute malaria in most regions, SP has been successfully repurposed into a cornerstone of modern malaria prevention. As the sole WHO-recommended agent for Intermittent Preventive Treatment in pregnancy (IPTp) and a key component of Seasonal Malaria Chemoprevention (SMC), SP is responsible for preventing millions of malaria cases and saving thousands of lives among the most vulnerable populations—pregnant women, infants, and young children—every year. This transition from a "firefighting" treatment to a "fire prevention" prophylactic represents a critical lesson in the adaptive management of infectious diseases.

The continued utility of SP is, however, under constant threat. The spread of parasites carrying multiple mutations in the pfdhfr and pfdhps genes, particularly the "sextuple mutant" haplotype, is progressively eroding the drug's efficacy, even for prevention. This reality underscores the critical importance of robust, continuous molecular surveillance to monitor resistance patterns and inform evidence-based public health policy. National and global health bodies must remain vigilant, using this data to identify regions where the benefits of SP may be compromised and alternative strategies are needed.

In conclusion, Sulfadoxine-Pyrimethamine remains an indispensable, albeit imperfect, tool in the malaria control arsenal. Its story is a powerful illustration of the dynamic interplay between pharmacology, parasite evolution, and public health strategy. While its future is uncertain, its present-day impact is undeniable. The ongoing challenge for the global health community is to maximize the benefits of this valuable drug for as long as possible, while urgently pursuing the development of new and effective alternatives to secure the health of future generations in malaria-endemic regions.

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