Drug Monograph
Trimethoprim-Sulfamethoxazole
Co-trimoxazole — Brand names: Bactrim, Bactrim DS, Septra, Sulfatrim
Pharmacokinetic Profile
Half-Life
TMP 8–10 h; SMX 10 h
Metabolism
SMX: hepatic (N4-acetylation, CYP2C9); TMP: hepatic (oxidation)
Protein Binding
SMX ~70%; TMP ~44%
Bioavailability
Rapid, near-complete oral absorption
Volume of Distribution
TMP 1.0–1.8 L/kg; SMX 0.14–0.26 L/kg
Clinical Information
Drug Class
Folate pathway inhibitor combination (sulfonamide + diaminopyrimidine)
Available Doses
SS tab (SMX 400 / TMP 80 mg); DS tab (SMX 800 / TMP 160 mg); Suspension (SMX 200 / TMP 40 mg per 5 mL); IV (SMX 80 / TMP 16 mg per mL)
Route
Oral, Intravenous
Renal Adjustment
Yes — CrCl 15–30: half dose; CrCl <15: avoid
Hepatic Adjustment
Contraindicated in marked hepatic damage
Pregnancy
Avoid — risk of neural tube defects (folate antagonism); kernicterus risk near term
Lactation
Caution — excreted in breast milk; avoid in jaundiced, premature, or G6PD-deficient infants
Schedule / Legal Status
Prescription only (Rx)
Generic Available
Yes
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Urinary tract infections (E. coli, Klebsiella, Enterobacter, Morganella morganii, Proteus spp.) | Adults & children ≥2 months | Monotherapy | FDA Approved |
| Acute otitis media (S. pneumoniae, H. influenzae) | Children ≥2 months | Monotherapy | FDA Approved |
| Acute exacerbation of chronic bronchitis (S. pneumoniae, H. influenzae) | Adults | Monotherapy | FDA Approved |
| Shigellosis (S. flexneri, S. sonnei) | Adults & children ≥2 months | Monotherapy | FDA Approved |
| Pneumocystis jirovecii pneumonia (PJP) — treatment & prophylaxis | Adults & children ≥2 months | Monotherapy | FDA Approved |
| Traveler’s diarrhea (enterotoxigenic E. coli) | Adults | Monotherapy | FDA Approved |
Trimethoprim-sulfamethoxazole remains one of the most versatile antibiotics available. Its dual mechanism of folate pathway blockade yields synergistic antimicrobial activity at achievable serum concentrations, and the drug penetrates well into lung, prostate, CSF, and soft tissue compartments. For uncomplicated UTIs, current IDSA guidance supports a 3-day course as a first-line option where local resistance rates remain below 20%.
Notable Off-Label Uses
MRSA skin and soft tissue infections — IDSA-recommended option for mild-to-moderate purulent SSTIs. 1 DS tablet BID for 7–10 days. Evidence quality: High.
Stenotrophomonas maltophilia infections — Considered first-line agent by IDSA AMR guidance. IV dosing at 15 mg/kg/day (TMP component). Evidence quality: Moderate.
Nocardia infections — Drug of choice for pulmonary and disseminated nocardiosis. Duration typically 6–12 months. Evidence quality: Moderate.
Toxoplasma gondii prophylaxis — 1 DS tablet daily for Toxoplasma IgG-positive patients with HIV and CD4 <100 cells/mm³ (HHS OI guidelines). Evidence quality: High.
Cystoisospora (Isospora) belli — CDC-recommended preferred treatment. Evidence quality: Moderate.
Acute bacterial prostatitis — Recommended oral step-down option due to excellent prostatic penetration. Evidence quality: Moderate.
Granuloma inguinale (donovanosis) — CDC-recommended alternative agent. Evidence quality: Low.
Dosing
Doses below are expressed as trimethoprim (TMP) / sulfamethoxazole (SMX). One DS tablet = 160/800 mg; one SS tablet = 80/400 mg. The fixed-ratio combination maintains a 1:5 (TMP:SMX) ratio in all formulations.
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Uncomplicated UTI (cystitis) | 1 DS tab BID | 1 DS tab BID | 1 DS tab BID | 3-day course preferred for uncomplicated cystitis; 10–14 days for complicated UTI Check local E. coli resistance rates; avoid if >20% |
| Acute bacterial prostatitis — oral step-down | 1 DS tab BID | 1 DS tab BID | 1 DS tab BID | Total duration 2–4 weeks (acute) or 6–12 weeks (chronic) Excellent prostatic tissue penetration |
| Acute exacerbation of chronic bronchitis | 1 DS tab BID | 1 DS tab BID | 1 DS tab BID | 14-day course Reserve for culture-directed therapy |
| Shigellosis & traveler’s diarrhea | 1 DS tab BID | 1 DS tab BID | 1 DS tab BID | 5-day course |
| MRSA skin & soft tissue infection | 1–2 DS tab BID | 1–2 DS tab BID | 2 DS tab BID | 7–10 days; 1 DS tab BID likely sufficient for most SSTIs IDSA SSTI guidelines 2014 |
| PJP treatment — moderate to severe | 15–20 mg/kg/day TMP in 3–4 divided doses | 15–20 mg/kg/day TMP | 20 mg/kg/day TMP | 14–21 days; IV preferred initially for moderate-severe disease Add corticosteroids if PaO2 <70 mmHg or A-a gradient ≥35 |
| PJP prophylaxis — HIV (CD4 <200) | 1 DS tab daily | 1 DS tab daily | 1 DS tab daily | Continue until CD4 >200 for ≥3 months on ART Alternatives: 1 SS tab daily or 1 DS tab 3×/week |
| Toxoplasma prophylaxis (CD4 <100, IgG+) | 1 DS tab daily | 1 DS tab daily | 1 DS tab daily | Provides dual PJP + Toxoplasma coverage HHS OI guidelines |
| Stenotrophomonas maltophilia — treatment | 15 mg/kg/day TMP IV in 3–4 divided doses | 15 mg/kg/day TMP | 20 mg/kg/day TMP | Duration: 7–14 days depending on site and clinical response IDSA AMR guidance 2024 |
| Nocardia — pulmonary (non-disseminated) | 5–15 mg/kg/day TMP in 2–4 divided doses | 5–10 mg/kg/day TMP | 15 mg/kg/day TMP | Total duration 6–12 months; higher doses historically used but recent data supports intermediate dosing Consider SMX serum concentration monitoring |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| UTI / Otitis media / Shigellosis | 8 mg/kg/day TMP + 40 mg/kg/day SMX in 2 divided doses | Same | 320 mg TMP/day | UTI/otitis: 10 days; shigellosis: 5 days Age ≥2 months required; use weight-based suspension dosing |
| PJP treatment | 15–20 mg/kg/day TMP in 3–4 divided doses | Same | 20 mg/kg/day TMP | 14–21 days |
| PJP prophylaxis | 150 mg/m²/day TMP + 750 mg/m²/day SMX in 2 divided doses | Same | 320 mg TMP/day | Given on 3 consecutive days per week CDC pediatric OI guidelines |
Renal Dose Adjustment
| CrCl (mL/min) | Dose Adjustment | Maximum Dose | Dialysis Considerations | Notes |
|---|---|---|---|---|
| >30 | Standard dose | Per indication | — | No adjustment needed |
| 15–30 | 50% of standard dose | 50% of usual max | — | Monitor renal function and potassium closely |
| <15 | Not recommended | — | HD: 1 SS tab q24h or 1 DS tab post-dialysis 3×/week | Hemodialysis only moderately effective at removing drug |
Clinical Pearl: Dosing Convention
Prescriptions are typically written as TMP component. When the label says “15–20 mg/kg/day,” this refers to the trimethoprim portion; the sulfamethoxazole follows in the fixed 1:5 ratio (75–100 mg/kg/day SMX). For a 70 kg adult with PJP, this translates to approximately 2.5 DS tablets every 6 hours at the upper range — a substantial pill burden that often requires IV administration initially.
Pharmacology
Mechanism of Action
Trimethoprim-sulfamethoxazole achieves synergistic antimicrobial activity by sequentially blocking two enzymes in the bacterial folate biosynthesis pathway. Sulfamethoxazole competitively inhibits dihydropteroate synthase, the enzyme that incorporates para-aminobenzoic acid (PABA) into dihydrofolic acid. Trimethoprim then blocks the next step by reversibly inhibiting dihydrofolate reductase, which converts dihydrofolic acid to tetrahydrofolic acid. This dual blockade starves the bacterium of the tetrahydrofolate required for thymidine and purine nucleotide synthesis, halting DNA replication. The selectivity for bacterial over mammalian dihydrofolate reductase is approximately 50,000-fold, which accounts for the favorable therapeutic index at standard doses. The combination reduces the likelihood of resistance emergence compared with either agent alone, as bacteria must simultaneously develop mutations in both target enzymes.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid, near-complete; Tmax 1–4 h for both components; food does not significantly affect absorption | Oral and IV doses are essentially interchangeable for bioavailability; oral step-down straightforward |
| Distribution | TMP: Vd 1.0–1.8 L/kg; SMX: Vd 0.14–0.26 L/kg; both distribute to sputum, vaginal fluid, middle ear fluid, prostatic tissue, and CSF; crosses placenta | TMP’s large Vd and lipophilicity drive excellent tissue penetration including lungs, prostate, and CNS — key advantage for deep-seated infections |
| Metabolism | SMX: hepatic N4-acetylation (major), CYP2C9-mediated N4-hydroxylation; TMP: hepatic oxidation to 1- and 3-oxides, 3′- and 4′-hydroxy derivatives | SMX inhibits CYP2C9; TMP inhibits CYP2C8 and OCT2 transporter — basis for multiple clinically significant drug interactions |
| Elimination | Primarily renal; 84.5% of SMX (30% as free drug) and 66.8% of TMP recovered in urine within 72 h; t½ SMX 10 h, TMP 8–10 h | Achieves very high urinary concentrations, supporting efficacy in UTIs; half-life prolonged significantly in renal impairment requiring dose reduction |
Side Effects
≥10%
Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Gastrointestinal symptoms (nausea, vomiting, anorexia) | 20–43% | Most common reason for complaints; higher rates at PJP treatment doses; generally mild and self-limiting at standard doses |
| Rash (maculopapular, urticarial) | 3–34% | Incidence highly variable: ~3–5% in general population, up to 30–34% in HIV-positive patients; warrants immediate evaluation for progression to severe cutaneous reaction |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 3–8% | Usually mild; evaluate for C. difficile if persists beyond therapy |
| Hyperkalemia | 5–8% | TMP blocks ENaC in distal nephron (amiloride-like effect); higher incidence in elderly, renal impairment, or concurrent ACE inhibitor/ARB use |
| Elevated serum creatinine (non-renal) | ~5% | TMP competitively inhibits creatinine secretion via OCT2; rises 0.1–0.5 mg/dL; does not reflect true GFR decline. Reversible on discontinuation |
| Headache | 3–5% | Usually mild; adequate hydration may help |
| Photosensitivity | 1–3% | Counsel sun avoidance and sunscreen use |
| Fever (drug fever) | 1–5% | More common in HIV-positive patients; must differentiate from infection progression |
| Leukopenia / mild cytopenias | 1–5% | Dose-related folate antagonism; more frequent with prolonged courses or pre-existing folate deficiency |
Serious
Serious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Stevens-Johnson syndrome / Toxic epidermal necrolysis (SJS/TEN) | Rare (~1–5 per million prescriptions) | 4–28 days after initiation | Immediate discontinuation; urgent dermatology and burns center referral; do NOT re-challenge |
| DRESS syndrome | Rare | 2–8 weeks | Discontinue immediately; systemic corticosteroids may be required; monitor for organ involvement |
| Agranulocytosis / aplastic anemia | Rare (~1 per 20,000–100,000) | 2–12 weeks | Discontinue; CBC monitoring; leucovorin 5–15 mg/day may accelerate recovery; hematology consultation |
| Hemolytic anemia (G6PD-deficient patients) | Uncommon (dose-related in G6PD-deficient individuals) | Days to weeks | Discontinue; consider G6PD screening in at-risk populations before prescribing |
| Acute kidney injury / interstitial nephritis | Uncommon (<1%) | Days to weeks | Discontinue; supportive care; differentiate from benign creatinine rise (OCT2 inhibition) |
| Fulminant hepatic necrosis | Very rare | 1–6 weeks | Discontinue immediately; hepatology consultation; supportive measures |
| Severe hyperkalemia (>6.0 mEq/L) | Uncommon (higher risk in renal impairment + ACEi/ARB) | 3–7 days | Check potassium within 3–5 days of initiation in at-risk patients; discontinue if severe; standard hyperkalemia management |
| Anaphylaxis / circulatory shock | Rare | Minutes to hours (especially on re-challenge) | Emergency management (epinephrine, IV fluids, vasopressors); permanent discontinuation; document allergy |
| Severe pulmonary reactions (respiratory failure, eosinophilic pneumonia) | Very rare | Days to weeks | Discontinue; respiratory support; reported cases requiring mechanical ventilation or ECMO (FDA 2024 labeling update) |
| Hemophagocytic lymphohistiocytosis (HLH) | Very rare | Variable | Discontinue; check ferritin, triglycerides, fibrinogen; hematology/immunology referral (FDA 2024 labeling update) |
| Clostridioides difficile-associated diarrhea | Uncommon | During or up to 2 months after therapy | Discontinue causative antibiotic; test for C. difficile toxin; treat per IDSA guidelines |
Discontinuation
Discontinuation Rates
Standard-Dose Courses (General Population)
~1.9% vs 0.6% placebo
Top reasons: GI intolerance, rash, allergic reaction
High-Dose PJP Treatment (HIV Patients)
20–57%
Top reasons: Rash, fever, leukopenia, hepatotoxicity, hyperkalemia; rates are markedly higher in AIDS patients compared with the general population
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Rash | 1–15% | Lower end at standard doses; upper end in HIV patients on PJP treatment |
| GI intolerance | 1–5% | Nausea and vomiting most common; taking with food may help |
| Cytopenias | 1–10% | More frequent with high-dose or prolonged use; monitoring essential |
| Hepatotoxicity | <1–5% | Transaminase elevation; higher in immunocompromised patients |
Managing Rash in HIV Patients
Rash occurs in up to one-third of HIV-positive patients receiving TMP-SMX for PJP treatment or prophylaxis. Mild rashes (maculopapular, non-progressive) can sometimes be managed with antihistamines while continuing therapy under close observation, as many patients develop tolerance. However, any rash accompanied by mucosal involvement, blistering, fever, hepatitis, or eosinophilia mandates immediate drug discontinuation and evaluation for SJS/TEN or DRESS. For patients with prior mild reactions requiring PJP prophylaxis, desensitization protocols over 3–7 days have demonstrated success rates of 60–80%.
Drug Interactions
Trimethoprim-sulfamethoxazole has a clinically significant interaction profile driven by two distinct mechanisms: TMP inhibits CYP2C8 and the OCT2 renal transporter, while SMX inhibits CYP2C9. Together, these enzymes affect the metabolism of warfarin, phenytoin, oral hypoglycemics, methotrexate, and several cardiac drugs. Potassium-elevating interactions are also important due to TMP’s amiloride-like activity at ENaC.
Major
Warfarin
MechanismSMX inhibits CYP2C9-mediated S-warfarin metabolism; SMX may also displace warfarin from albumin
EffectIncreased INR and bleeding risk; TMP-SMX prolonged phenytoin half-life by 39% in studies (same CYP pathway relevance)
ManagementCheck INR within 3–5 days of starting; consider empiric 10–25% warfarin dose reduction; monitor INR frequently during and after course
FDA PI
Major
Dofetilide
MechanismTMP inhibits OCT2-mediated renal secretion of dofetilide
EffectElevated dofetilide levels; risk of QT prolongation and torsade de pointes
ManagementConcomitant use is contraindicated per FDA labeling; choose alternative antibiotic
FDA PI
Major
Methotrexate
MechanismSMX displaces methotrexate from protein binding and competes for renal tubular secretion; additive antifolate toxicity
EffectIncreased free methotrexate concentrations; heightened myelosuppression risk
ManagementAvoid concurrent use; if unavoidable, monitor CBC closely and consider leucovorin rescue (but note: leucovorin is contraindicated during PJP treatment)
FDA PI
Major
Leucovorin (during PJP treatment)
MechanismPharmacodynamic antagonism of TMP-SMX antimicrobial activity against P. jirovecii
EffectIncreased treatment failure and mortality observed in RCT (Safrin et al., 1994)
ManagementDo NOT co-administer leucovorin with TMP-SMX for PJP treatment; leucovorin is acceptable after TMP-SMX is completed or for non-PJP indications
FDA PI / RCT
Moderate
ACE Inhibitors / ARBs / Potassium-Sparing Diuretics
MechanismAdditive potassium retention; TMP’s amiloride-like blockade of ENaC combined with RAAS inhibition
EffectClinically significant hyperkalemia; risk of cardiac arrhythmia; particularly dangerous in elderly with renal impairment
ManagementCheck potassium at baseline and within 3–5 days; monitor ECG in high-risk patients; avoid or use short courses if possible
FDA PI / Case Series
Moderate
Phenytoin
MechanismSMX inhibits CYP2C9-mediated phenytoin metabolism
EffectIncreased phenytoin half-life (~39%) and reduced metabolic clearance (~27%); risk of phenytoin toxicity (ataxia, nystagmus)
ManagementMonitor serum phenytoin levels; watch for signs of toxicity; may need temporary phenytoin dose reduction
FDA PI
Moderate
Oral Hypoglycemics (sulfonylureas, metformin, glitazones)
MechanismSMX inhibits CYP2C9 (glipizide, glyburide); TMP inhibits OCT2 (metformin renal clearance); SMX inhibits CYP2C8 (pioglitazone, repaglinide)
EffectHypoglycemia; risk greater in patients with renal dysfunction, liver disease, or malnutrition
ManagementIncrease blood glucose monitoring frequency; counsel patient on hypoglycemia symptoms; consider temporary dose reduction of oral hypoglycemic
FDA PI
Moderate
Cyclosporine
MechanismAdditive nephrotoxicity; possible pharmacokinetic interaction reducing cyclosporine efficacy
EffectReversible nephrotoxicity reported in renal transplant recipients
ManagementAvoid concurrent use if possible; if necessary, monitor renal function and cyclosporine levels closely
FDA PI
Moderate
Procainamide
MechanismTMP inhibits renal tubular secretion of procainamide and its active metabolite NAPA via OCT2
EffectElevated procainamide/NAPA levels; QTc prolongation; risk of torsade de pointes
ManagementMonitor procainamide and NAPA levels; ECG monitoring; clinical observation for signs of toxicity
FDA PI
Moderate
Digoxin
MechanismTMP may reduce renal clearance of digoxin; possible P-gp interaction
EffectIncreased digoxin blood levels, particularly in elderly patients
ManagementMonitor serum digoxin levels; watch for toxicity signs (nausea, visual changes, arrhythmia)
FDA PI
Minor
Thiazide Diuretics
MechanismUnknown; possible immunologic mechanism
EffectIncreased incidence of thrombocytopenia with purpura, particularly in elderly patients
ManagementMonitor platelet count in elderly patients on concurrent thiazides; consider alternative diuretic or antibiotic
FDA PI
Minor
Tricyclic Antidepressants
MechanismUncertain; possible altered TCA metabolism
EffectReduced TCA efficacy reported
ManagementMonitor therapeutic response; adjust TCA dose accordingly if needed
FDA PIMonitoring
-
Complete Blood Count
Baseline; weekly for courses >14 days; frequently for high-dose regimens
Routine Monitor for leukopenia, thrombocytopenia, megaloblastic anemia, and agranulocytosis. Folate-deficient patients and those on prolonged therapy are at highest risk. Discontinue if significant reduction in any formed blood element. -
Renal Function
Baseline; during therapy as clinically indicated
Routine Serum creatinine, BUN, and urinalysis with microscopy. Remember that TMP raises serum creatinine ~0.1–0.5 mg/dL via OCT2 inhibition without true GFR change. If creatinine rises disproportionately, investigate true renal injury. -
Serum Potassium
Within 3–5 days of initiation in at-risk patients
Trigger-based At-risk groups: elderly, renal impairment, concurrent ACE inhibitors/ARBs/potassium-sparing diuretics, high-dose TMP (PJP treatment). TMP blocks ENaC in an amiloride-like fashion. -
Hepatic Function
Baseline for prolonged courses; as clinically indicated
Trigger-based Transaminases and bilirubin. Risk of cholestatic hepatitis and fulminant hepatic necrosis. Discontinue if clinically significant elevations develop. -
Serum Sodium
As clinically indicated, especially during PJP treatment
Trigger-based Severe hyponatremia reported, particularly during high-dose PJP treatment. Evaluate for hyponatremia in symptomatic patients (confusion, seizures). -
INR / Prothrombin Time
Within 3–5 days of initiation in patients on warfarin
Trigger-based SMX potentiates warfarin via CYP2C9 inhibition. Close INR monitoring essential; anticipate need for warfarin dose reduction. -
Blood Glucose
During therapy in patients on oral hypoglycemics
Trigger-based TMP-SMX potentiates sulfonylureas and metformin; cases of hypoglycemia reported in non-diabetic patients as well, particularly those with renal dysfunction or malnutrition. -
Skin & Mucous Membranes
Continuous clinical observation throughout therapy
Routine Educate patients on early signs of serious cutaneous reactions (rash with mucosal involvement, blistering, fever). Discontinue immediately at first sign of skin rash per FDA labeling.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to trimethoprim or any sulfonamide
- History of drug-induced immune thrombocytopenia with prior trimethoprim or sulfonamide use
- Documented megaloblastic anemia due to folate deficiency
- Marked hepatic damage
- Severe renal insufficiency (CrCl <15 mL/min) when renal function cannot be monitored
- Infants younger than 2 months
- Concurrent dofetilide use (risk of fatal arrhythmia)
Relative Contraindications (Specialist Input Recommended)
- Pregnancy (especially first trimester) — associated with neural tube defects, cardiovascular malformations; use only if no alternative and benefit clearly outweighs risk; supplement with folate
- Breastfeeding jaundiced, premature, or G6PD-deficient infants — risk of bilirubin displacement and kernicterus
- G6PD deficiency — dose-related hemolysis with sulfonamide component; consider alternative if possible
- Concurrent methotrexate therapy — additive myelosuppression and increased free methotrexate levels
- Concurrent high-dose pyrimethamine (>25 mg/week) — risk of megaloblastic anemia
- Porphyria — sulfonamides may precipitate crisis
Use with Caution
- Impaired renal function (CrCl 15–30 mL/min) — dose reduction required; half-life of both components prolonged
- Pre-existing folate deficiency — elderly, chronic alcoholism, malabsorption, malnutrition, concurrent anticonvulsants
- Elderly patients — increased risk of severe cutaneous reactions, thrombocytopenia, hyperkalemia, and bone marrow suppression
- Patients on ACE inhibitors, ARBs, or potassium-sparing diuretics — risk of hyperkalemia
- Severe allergies or bronchial asthma — higher incidence of hypersensitivity reactions
- Thyroid dysfunction — sulfonamides may have goitrogenic effects
- HIV/AIDS patients — significantly higher rates of adverse reactions compared with general population
FDA Safety Communication (2024 Labeling Update)
Severe Cutaneous Adverse Reactions, Pulmonary Injury, Circulatory Shock, and HLH
The 2024 updated FDA labeling for TMP-SMX products adds warnings for hemophagocytic lymphohistiocytosis (HLH), severe pulmonary reactions including respiratory failure requiring mechanical ventilation or ECMO, and circulatory shock on re-challenge. Fatalities have occurred with severe cutaneous adverse reactions (SJS, TEN, DRESS, AGEP, AFND), fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and anaphylaxis. Discontinue immediately at the first appearance of skin rash or any sign of a serious adverse reaction.
Patient Counselling
Purpose of Therapy
Trimethoprim-sulfamethoxazole is an antibiotic combination used to treat or prevent bacterial infections. It works by blocking two steps in bacterial folic acid production, which bacteria need to grow and multiply. It does not treat viral infections such as colds or influenza. Taking the full prescribed course is essential even if symptoms improve before the medication is finished, as stopping early may allow bacteria to survive and develop resistance.
How to Take
Take each dose with a full glass of water and drink several additional glasses of water throughout the day to help prevent crystal formation in the urine. The drug can be taken with or without food, though taking it with food may reduce stomach upset. If using the liquid suspension, measure each dose carefully with the provided measuring device rather than a household spoon.
Skin Rash or Allergic Reaction
Tell patient
Rash is one of the most common reasons people need to stop this medication. Most rashes are mild, but some can become serious. Any rash that develops during treatment needs to be evaluated promptly.
Call prescriber
Stop the medication immediately and seek urgent medical attention if you develop: a rash with blistering or peeling skin, mouth sores, sore throat with fever, swelling of the face or tongue, or difficulty breathing. These may be signs of a serious allergic reaction.
Gastrointestinal Side Effects
Tell patient
Nausea, vomiting, and loss of appetite are common, especially during the first few days. Taking the medication with food and maintaining good hydration typically helps reduce these symptoms.
Call prescriber
Contact your doctor if you develop watery or bloody diarrhea, which can occur during treatment or even weeks afterward, as this may indicate a Clostridioides difficile infection requiring different treatment.
Sun Sensitivity
Tell patient
This medication can make your skin more sensitive to sunlight. You may burn more easily than usual. Use sunscreen (SPF 30+), wear protective clothing, and avoid prolonged sun exposure while taking the drug.
Call prescriber
If you develop a severe sunburn with blistering, extensive redness, or a rash in sun-exposed areas, contact your prescriber.
Hydration & Kidney Protection
Tell patient
Drinking plenty of water (at least 6–8 glasses per day) is important to prevent crystal formation in the kidneys and urinary tract. This is especially important in warm weather or if you exercise heavily.
Call prescriber
Contact your doctor if you notice reduced urine output, blood in the urine, or flank pain, which may indicate kidney crystal formation.
Signs of Blood Disorders
Tell patient
This medication can occasionally affect blood cell production. This is more likely during longer courses or in people with certain nutritional deficiencies.
Call prescriber
Seek medical attention if you develop unusual bruising, bleeding gums, persistent sore throat, fever, extreme fatigue, or pallor, as these could indicate blood cell abnormalities.
Low Blood Sugar (Patients on Diabetes Medications)
Tell patient
TMP-SMX can increase the effect of some diabetes medications, leading to blood sugar levels that are lower than expected. Monitor your blood glucose more frequently while taking this antibiotic.
Call prescriber
If you experience shakiness, sweating, confusion, dizziness, or rapid heartbeat, check your blood sugar and contact your prescriber if readings are consistently low.
Sources
Regulatory (PI / SmPC)
- Bactrim (sulfamethoxazole and trimethoprim) tablets, USP. Full Prescribing Information. Sun Pharmaceutical Industries, Inc. Revised June 2024. FDA Label Primary regulatory reference for all approved indications, dosing, contraindications, adverse reactions, and drug interactions.
- FDA Drug Safety-related Labeling Changes for Sulfamethoxazole and Trimethoprim (2024). FDA SrLC Details the 2024 labeling update adding warnings for HLH, severe pulmonary reactions, and circulatory shock on re-challenge.
- Sulfamethoxazole and Trimethoprim Oral Suspension. Full Prescribing Information. Revised 2024. FDA Label Regulatory label for suspension formulation; includes updated 2024 safety warnings consistent with the tablet label.
Key Clinical Trials
- Talan DA, Mower WR, Krishnadasan A, et al. Trimethoprim-sulfamethoxazole versus placebo for uncomplicated skin abscess. N Engl J Med. 2016;374(9):823–832. DOI Landmark RCT (n=1265) demonstrating TMP-SMX superiority over placebo for drained skin abscesses; provided key safety data for standard-dose therapy.
- Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994;170(4):912–917. DOI Seminal RCT establishing the contraindication of leucovorin co-administration during PJP treatment with TMP-SMX.
- Hatzl S, Posch F, Scholz L, et al. Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV: a systematic review and network meta-analysis. Clin Microbiol Infect. 2025. DOI Recent network meta-analysis confirming TMP-SMX as the most effective PJP treatment regimen with quantified adverse event comparisons.
Guidelines
- Tamma PD, Heil EL, Justo JA, et al. IDSA 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. 2024;ciae403. DOI Current IDSA AMR guidance recommending TMP-SMX as first-line for Stenotrophomonas maltophilia and as an oral step-down option for ESBL-E UTIs.
- Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18–e55. DOI IDSA MRSA guidelines recommending TMP-SMX as a treatment option for mild-to-moderate purulent SSTIs.
- HHS Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. HHS Guidelines Provides current recommendations for TMP-SMX dosing for PJP treatment, PJP prophylaxis, and Toxoplasma prophylaxis in HIV patients.
Mechanistic / Basic Science
- Masters PA, O’Bryan TA, Zurlo J, et al. Trimethoprim-sulfamethoxazole revisited. Arch Intern Med. 2003;163(4):402–410. DOI Comprehensive review of TMP-SMX pharmacology, spectrum of activity, and clinical applications including mechanism of folate pathway inhibition.
- Wormser GP, Keusch GT, Heel RC. Co-trimoxazole (trimethoprim-sulfamethoxazole): an updated review of its antibacterial activity and clinical efficacy. Drugs. 1982;24(6):459–518. DOI Classic drug review establishing the mechanistic basis of TMP-SMX synergy and the 50,000-fold selectivity for bacterial over mammalian dihydrofolate reductase.
Pharmacokinetics / Special Populations
- Kremers P, Duvivier J, Heusghem C. Pharmacokinetic studies of co-trimoxazole in man after single and repeated doses. J Clin Pharmacol. 1974;14(2):112–117. DOI Foundational PK study establishing steady-state plasma levels, urinary recovery, and bioequivalence data for the TMP-SMX combination.
- Varoquaux O, Lajoie D, Gobert C, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985;20(6):575–581. DOI Key study demonstrating reduced TMP renal clearance in geriatric patients, supporting dose adjustment recommendations in the elderly.
- Preyra D, Garg AX, Engel MS, et al. Safety of sulfamethoxazole-trimethoprim for the treatment of bacterial infection in outpatient settings: a systematic review and meta-analysis. Br J Clin Pharmacol. 2025;e70051. DOI Recent systematic review with disproportionality analysis quantifying adverse event signals including hyperkalemia, SJS/TEN, and acute kidney injury.