Version May 2024
INTRODUCTION — Trimethoprim-sulfamethoxazole (TMP-SMX), also known as co-trimoxazole, is a combination of two antimicrobial agents that act synergistically against a wide variety of bacteria. Although other combinations of sulfonamides are available with trimethoprim, TMP-SMX is by far the most widely used.
This topic will review basic issues related to the clinical use of trimethoprim-sulfamethoxazole. The multiple clinical settings in which this combination may be used are discussed separately in the appropriate topic reviews.
MECHANISM OF ACTION — The two components, TMP and SMX, work sequentially to inhibit enzyme systems involved in the bacterial synthesis of tetrahydrofolic acid (THF) [1,2].
●SMX is a structural analog of para-aminobenzoic acid (PABA) and competes with PABA to inhibit the synthesis of dihydrofolic acid, an intermediate step in the formation of THF [1,3]. SMX binds to dihydropteroate synthetase which catalyses this reaction [3].
●TMP binds to bacterial dihydrofolate reductase (in preference to human dihydrofolate reductase), also preventing the formation of THF [4].
Reduced availability of THF inhibits thymidine synthesis and subsequently DNA synthesis [1,2]. Thus, small amounts of thymidine (present in vivo or in vitro) can reverse the activity of TMP-SMX.
RESISTANCE — Due to the widespread use of trimethoprim-sulfamethoxazole (TMP-SMX), resistance has developed in most bacterial species worldwide [1,2,5-8]. A variety of mechanisms have been described:
●Some bacteria have a decreased permeability for TMP-SMX, or have a target enzyme with decreased affinity for the drugs. As examples, resistance of Pneumocystis jirovecii to SMX after the administration of TMP-SMX has been correlated with dihydropteroate synthase gene mutations [9], while dihydrofolate reductase gene mutations account for high-level resistance in other organisms such as Enterococcus faecalis and Campylobacter jejuni. Impaired permeability has been demonstrated in resistant strains of Klebsiella pneumoniae and Serratia marcescens [4,10-12].
●Among enteric gram-negative bacteria, resistance is most often due to acquisition of plasmids with genes that encode drug resistant enzymes. These plasmids often carry genes that also confer resistance to other classes of antimicrobials [13]. Gene-mediated resistance is being increasingly noted in strains of Escherichia coli with resistance rates greater than 20 percent in many areas of the United States. Thus, the risk of E. Coli resistance must be considered before using TMP-SMX as empiric therapy (eg, for urinary tract infections) [14,15]. (See "Acute simple cystitis in adult and adolescent males", section on 'Treatment' and "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Management'.)
●Some bacteria (eg, Pseudomonas aeruginosa) have an active efflux mechanism to eliminate the drug from the cell [16].
●Naturally resistant bacteria to SMX (eg, E. faecalis) are typically auxotrophic for folic acid.
Maximal synergistic action occurs when microorganisms are susceptible to both drugs. Thus, bacteria naturally resistant to TMP at low levels and susceptible to SMX can be inhibited by the combination and vice-versa.
SPECTRUM OF ACTIVITY — TMP-SMX is effective against a wide variety of aerobic gram-positive and gram-negative bacteria, P. jirovecii, and some protozoa (table 1) [1,2,5,6,8,17-19]. As examples:
●Most methicillin-resistant Staphylococcus aureus are susceptible to TMP-SMX, particularly those that are community-acquired (eg, USA300 clone). (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)
●Certain pathogens that are nosocomially acquired and/or are seen in immunocompromised patients are frequently inhibited by TMP-SMX. These include Burkholderia cepacia (formerly Pseudomonas cepacia), Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia), Serratia marcescens, P. jirovecii, and Nocardia spp. (See "Bacterial infections following lung transplantation", section on 'Burkholderia cepacia' and "Stenotrophomonas maltophilia" and "Infections due to Serratia species".)
However, many pathogens are typically resistant to TMP-SMX. These include Pseudomonas aeruginosa, Bacteroides fragilis (and most other anaerobes), Mycobacterium tuberculosis, Treponema pallidum, Campylobacter, penicillin-resistant Streptococcus pneumoniae, and Rickettsiae. In addition, resistance can develop among previously susceptible bacteria, using the mechanisms described above. (See 'Resistance' above.)
PHARMACODYNAMICS AND PHARMACOKINETICS — Although trimethoprim (TMP) and sulfamethoxazole (SMX) are weak bactericidal agents when given alone, the combination is highly bactericidal against many bacteria [1,2,5,17,20]. Maximum synergistic inhibition of most susceptible bacteria occurs when the TMP-SMX concentration ratio is 1:20. The drug combination is prepared in a higher fixed ratio of 1:5; however, peak serum concentrations of 1:20 are still achieved by both oral and intravenous therapy because of the wider volume of distribution of TMP.
●Bioavailability and peak serum levels – Bioavailability of TMP-SMX is approximately 85 percent for both compounds. Absorption of TMP-SMX is not affected by food or other medications.
Peak serum levels of TMP-SMX after administration of a double-strength tablet are 1 to 2 microgram/mL and 25 to 60 microgram/mL, respectively. Peak concentrations are reached at two to four hours; peak concentrations are reached more quickly (one to two hours) with parenteral therapy. The concentrations achieved after intravenous administration of TMP-SMX equivalent to two DS tablets are 3.5 microgram/mL and 47.3 microgram/mL respectively.
●Distribution – TMP-SMX is widely distributed in the body including cerebrospinal fluid, vaginal fluid, sputum, middle ear fluid, bronchial secretions, placenta, and breast milk [21]. However, tissue concentrations are generally lower than serum concentrations. TMP is more lipophilic than SMX (apparent volume of distribution 100 to 120 L and 12 to 18 L respectively), resulting in ratios of 1:2 to 1:10 in tissues compared with 1:20 in the extracellular fluid. CSF penetration of TMP-SMX is generally good, with TMP concentrations ranging from 20 to 60 percent of serum values and SMX concentrations ranging from 12 to 50 percent of serum values. The approximate ratio of TMP-SMX in the CSF is 1:15.
●Metabolism and excretion – TMP-SMX is excreted in the urine with 50 percent of the drug eliminated in the first 24 hours. SMX is approximately 70 percent protein bound; it is acetylated (61 percent) and glucuronide-conjugated (15 percent) in the liver. In comparison, TMP is excreted unchanged, primarily in the urine, with up to 30 percent metabolized to six inactive metabolites [22].
Compromised renal function results in prolongation of the half-lives of each drug. Accumulation of TMP-SMX and metabolites occurs when creatinine clearance is less than 30 mL/minute necessitating dose adjustment. Uremic and hypoalbuminemic patients may have reduced protein binding and an increased volume of distribution of SMX component [23]. (See 'Renal dose adjustment' below.)
Overall, the kinetics of TMP-SMX are first order. The half-life for both compounds is 10 to 12 hours.
DOSAGE AND ADMINISTRATION
Approach for most patients — Multiple formulations of trimethoprim-sulfamethoxazole (TMP-SMX) are available for use:
●Oral single strength (SS) tablet – 80 mg TMP/400 mg SMX
●Oral double-strength tablet – 160 mg TMP/800 mg SMX
●Oral suspension – 40 mg TMP/200 mg SMX per 5 mL
●Intravenous – 80 mg TMP/400 mg SMX per 5 mL (16 mg/mL TMP; 80 mg/mL SMX).
Dosing of TMP-SMX is based on the trimethoprim component and expressed as a mg/kg per day of TMP. Oral doses of TMP-SMX are usually given as a SS or more commonly a DS tablet once to four times daily depending upon the indication and renal function [1,5,18,19,24,25].
Intravenous TMP-SMX must be mixed with dextrose in water at a maximum concentration of 5 mL TMP-SMX (equivalent to 80 mg TMP component) per 75 mL. At this concentration, the product is only stable for two hours. Five mL of TMP-SMX may also be mixed with 100 mL of 5 percent dextrose, which is stable for hours. A more standard concentration is 5 mL (equivalent to 80 mg TMP component) per 125 mL of 5 percent dextrose in water that retains stability for up to six hours [26]. All dilutions should be inspected for cloudiness and/or particulate formation prior to and during administration.
Therapeutic drug monitoring of TMP-SMX is not routinely done [27].
Renal dose adjustment — TMP-SMX dosing should be altered for patients with kidney insufficiency whose creatinine clearance is less than or equal to 30 mL per minute (calculator 1). It is generally recommended to provide 50 percent of the dose for patients with a creatinine clearance between 15 and 30 mL per minute.
The US Food and Drug Administration (FDA) prescribing information recommends against use of TMP-SMX in patients with a creatinine clearance less than 15 mL per minute due to risk of drug accumulation [26]. However, dose adjustment guidelines are available for patients with a creatinine clearance less than 15 mL per minute and for those receiving renal replacement therapy; these guidelines are useful when acceptable alternatives are lacking [23,28-30]. For specific recommendations, refer to the Lexicomp trimethoprim-sulfamethoxazole drug information topic section "Dosing: Kidney Impairment" within UpToDate.
Dosing in persons with obesity — Patients who are considered obese (typically defined as a body mass index (BMI) >30 kg/m2) may have altered pharmacokinetic parameters, such as increased volumes of distribution as a result of increases in adipose and lean muscle mass [31,32]. As such, weight-based dosing of trimethoprim-sulfamethoxazole in obesity (mg/kg of the TMP component) should be based on the adjusted body weight (calculator 2) [33]. However, tolerability may limit oral dosing, particularly when the calculated dose exceeds eight double strength tablets (ie, >1280 mg TMP component) per day.
Other considerations for determining the optimal dosing regimen include renal impairment, the specific pathogen, and the site of infection. (See 'Spectrum of activity' above and 'Pharmacodynamics and pharmacokinetics' above and 'Renal dose adjustment' above.)
Monitoring for clinical efficacy and toxicity is particularly important when using trimethoprim-sulfamethoxazole in this population [34].
ADVERSE EFFECTS AND PRECAUTIONS — Trimethoprim-sulfamethoxazole (TMP-SMX) is generally well tolerated in patients without HIV in whom adverse reactions occur in approximately 6 to 8 percent of individuals [5,18,35]. In comparison, the adverse reaction rate is as high as 25 to 50 percent in patients with HIV, with many of the reactions being severe [5,36-39]. Adverse effects from TMP-SMX can usually be managed by stopping the drug. However, for conditions in which TMP-SMX is considered first-line therapy (eg, Pneumocystis jirovecii pneumonia in patients with HIV), continued treatment with TMP-SMX may be indicated in the setting of non-life threatening adverse reactions [25]. (See 'Life threatening effects' below.)
Adverse effects — The more common adverse reactions to TMP-SMX involve the gastrointestinal tract (nausea, vomiting) and skin (rash and pruritus) (table 2). (See "Fever and rash in patients with HIV" and "Drug eruptions".)
Nephrotoxicity associated with TMP-SMX is uncommon; however, TMP is known to decrease the tubular secretion of creatinine. This can lead to an increase in serum creatinine that is not reflective of a true reduction in glomerular filtration rate [40]. (See "Drugs that elevate the serum creatinine concentration", section on 'Decreased secretion'.)
Other side effects that can occur include:
●Renal tubular acidosis [41] (see "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Antibiotics')
●Hepatitis [36]
●Hypoglycemia [42]
●Hyponatremia [43]
●Hemolysis in patients who have glucose-6-phosphate dehydrogenase deficiency [44] (see "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Inciting drugs, chemicals, foods, illnesses')
Life threatening effects — Life-threatening effects, which may be more likely to occur in patients with HIV and older adults, include neutropenia, anaphylaxis, and uncommon severe dermatologic reactions such as Stevens-Johnson syndrome (involving the mucosal surfaces), exfoliative dermatitis (a severe skin disorder with generalized erythema and scaling), and toxic epidermal necrolysis (an acute severe reaction with widespread erythema and detachment of the epidermis) [35,36,39,45].
Another potentially life-threatening side effect includes hyperkalemia due to blockade of the collecting tubule sodium channel by trimethoprim (an action similar to that induced by the potassium-sparing diuretic amiloride); this is most common in patients with HIV who are treated with high doses [46], but normal doses can produce a modest elevation in the plasma potassium concentration in subjects without HIV [47,48] (see "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Antibiotics'). Sudden death, possibly due to hyperkalemia, has been reported among older patients who were prescribed TMP-SMX while also receiving spironolactone, an angiotensin converting enzyme (ACE) inhibitor, or an angiotensin receptor blocker (ARB) [49,50]. As an example, in a case-control study of individuals taking ACE inhibitors or ARBs, those who received TMP-SMX had an increased seven-day risk of sudden death compared with those who received amoxicillin (adjusted odds ratio 1.38, 95% CI: 1.09 to 1.76) [49]. However, these studies have substantial limitations, and higher quality evidence is needed to confirm these findings.
An association with TMP-SMX and an increased risk of severe lactic acidosis has also been reported [51]. In this report, the only identifiable cause of lactic acidosis was the use of TMP-SMX, and the lactic acidosis resolved after discontinuation of the antibiotic, further supporting the association. Lactic acidosis due to TMP-SMX is felt to be a result of propylene glycol, which is used as a solvent in several medications, such as diazepam and intravenous TMP-SMX.
Precautions — Certain precautions should be taken when administering TMP-SMX to individuals with underlying comorbidities and/or past adverse reactions to this agent. Detailed information is available in the drug information topic on trimethoprim-sulfamethoxazole; examples include:
●Folate deficiency – TMP-SMX should be used with caution in patients with folate deficiency or those at risk for complications of folate deficiency (eg, pregnancy, chronic hemolytic anemia), because trimethoprim weakly inhibits human dihydrofolate reductase, an enzyme needed for folate recycling [52]. When given over long periods or in high doses, trimethoprim may cause megaloblastic changes (eg, macrocytic anemia, mild thrombocytopenia, leukopenia) by reducing folate available for hematopoiesis.
Both folic acid and leucovorin (folinic acid) can reduce the anti-folate activity of TMP-SMX caused by trimethoprim. In general, either supplement can be used without affecting the antimicrobial activity of TMP-SMX. However, in some settings (eg, treatment of certain opportunistic infections), supplementation is avoided or one is preferred over the other:
•In most patients with AIDS and Pneumocystis pneumonia, we do not supplement with folic acid or leucovorin because they have been associated with a higher risk of treatment failure [53]. However, for pregnant women with Pneumocystis pneumonia, folic acid supplementation should be used to reduce the risk of neural tube defects. (See 'Pregnancy and breastfeeding' below.)
•If supplementation is needed when TMP-SMX is used for the treatment of toxoplasmosis, leucovorin is preferred rather than folic acid because, unlike folic acid, leucovorin cannot be metabolized by the parasite.
Additional information about the use of TMP-SMX for the treatment and prevention of Pneumocystis pneumonia and toxoplasmosis is presented separately. (See "Treatment and prevention of Pneumocystis infection in patients with HIV" and "Toxoplasmosis in patients with HIV", section on 'Treatment'.)
●Sulfonamide allergy – TMP-SMX should not be administered to patients with a history of anaphylaxis or one of the blistering delayed reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis related to sulfonamides. (See 'Life threatening effects' above.)
However, there are certain settings where patients with a sulfonamide allergy may be able to receive TMP-SMX:
•Patients with an allergy to nonantimicrobial sulfonamides – There are two distinct groups of sulfonamides: antimicrobial sulfonamides and nonantimicrobial sulfonamides (table 3 and table 4). The risk of cross-reactivity between these groups is extremely low [54]. Thus, if a patient had a past allergic reaction to nonantimicrobial sulfonamides, they can often safely receive TMP-SMX. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Cross-reactivity'.)
•Patients with a non-life-threatening hypersensitivity to sulfonamides – Patients in whom TMP-SMX was previously discontinued because of non-life-threatening skin reactions, such as maculopapular rash without involvement of the mucous membranes, can be desensitized if repeat therapy with TMP-SMX is necessary [55,56]. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Desensitization'.)
PREGNANCY AND BREASTFEEDING
●Pregnancy – During certain stages of pregnancy, trimethoprim-sulfamethoxazole (TMP-SMX) should be avoided, if possible, as it may be associated with an increased risk of adverse events (see "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'):
•In general, TMP-SMX should be avoided in the first trimester of pregnancy since trimethoprim may interfere with folate metabolism and increase the risk of neural tube defects [57]. However, TMP-SMX should be used (along with supplemental folic acid) if the potential benefit to the mother outweighs the possible risk to the fetus (eg, a pregnant woman with HIV who requires prophylaxis/treatment for Pneumocystis pneumonia) [58,59]. (See "Prenatal evaluation of women with HIV in resource-rich settings", section on 'Chemoprophylaxis for opportunistic infections'.)
•TMP-SMX should also be avoided, if possible, in the last month of pregnancy, due to the ability of sulfonamides to displace bilirubin bound to serum albumin, thereby increasing free unconjugated bilirubin levels that could increase the risk of kernicterus in the neonate.
●Breastfeeding – TMP-SMX is excreted in the breast milk; however, mothers who are taking TMP-SMX can breastfeed healthy, full-term infants at least one month old. By contrast, breastfeeding while on TMP-SMX should be avoided in infants with glucose-6-phosphate dehydrogenase deficiency, and TMP-SMX should be used cautiously during breastfeeding if the infant is jaundiced, premature, or ill. All infants should be monitored for hemolysis and jaundice if they are breastfeeding while the mother is on TMP-SMX. This approach is consistent with recommendations from the American Academy of Pediatrics and the World Health Organization [60-62].
DRUG INTERACTIONS — Trimethoprim-sulfamethoxazole can interact with a variety of drugs that may require adjustment of therapy and/or more frequent monitoring [1,5,6,19,49]. Interacting drugs include oral anticoagulants (warfarin), cyclosporine, oral hypoglycemics, rifampin, dapsone, phenytoin, methenamine, and possibly angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Specific interactions of TMP-SMX with other medications may be determined using the drug interactions program included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on drug interactions.
SUMMARY AND RECOMMENDATIONS
●Spectrum of activity – Trimethoprim-sulfamethoxazole (TMP-SMX), also known as co-trimoxazole, is a combination of two antimicrobial agents that act synergistically against a wide variety of aerobic gram-positive and gram-negative bacteria, and some protozoa. It is also used as a first-line agent pathogen such as Stenotrophomonas maltophilia, Pneumocystis jirovecii, and Nocardia spp. (See 'Spectrum of activity' above.)
●Mechanism of action – The two components, TMP and SMX, work sequentially to inhibit enzyme systems involved in the bacterial synthesis of tetrahydrofolic acid (THF). Reduced availability of THF inhibits thymidine synthesis, which in turn inhibits DNA synthesis. (See 'Mechanism of action' above.)
Maximal synergistic action occurs when microorganisms are susceptible to both component drugs. However, bacteria that are resistant to one drug component, but remain fully susceptible to the other drug, can still be inhibited by the combination. (See 'Resistance' above.)
●Bioavailability – The bioavailability of TMP-SMX is approximately 85 percent for both compounds; absorption of TMP-SMX is not affected by food or other medications. (See 'Pharmacodynamics and pharmacokinetics' above.)
●Dosing and interactions – Dosing of TMP-SMX is based on the trimethoprim component and is expressed as a mg/kg per day of TMP. TMP-SMX can be administered orally or intravenously. Oral doses are usually given as a SS or DS tablets. The dose of TMP-SMX should be reduced for patients with whose creatinine clearance is less than or equal to 30 mL per minute (calculator 1). (See 'Dosage and administration' above.)
TMP-SMX can interact with a variety of drugs that may require adjustment of therapy and/or more frequent monitoring. (See 'Drug interactions' above.)
Detailed information on dose adjustments and drug interactions can be found in the drug interactions program within UpToDate.
●Adverse reactions – The most common adverse reactions to TMP-SMX involve the gastrointestinal tract (nausea, vomiting) and skin (rash and pruritus). (See 'Adverse effects' above.)
Life-threatening effects, which are more likely to occur in patients with HIV and older adults, include neutropenia, uncommon severe dermatologic reactions such as Stevens-Johnson syndrome, and toxic epidermal necrolysis. (See 'Life threatening effects' above.)
●Pregnancy – TMP-SMX should be avoided during certain stages of pregnancy, if possible. As an example, if used in the first trimester, the trimethoprim component may interfere with folate metabolism and increase the risk of neural tube defects. If used in the last month, sulfonamides can displace bilirubin bound to serum albumin, thereby increasing free unconjugated bilirubin levels that could increase the risk of kernicterus in the neonate. (See 'Pregnancy and breastfeeding' above.)
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