Trimethoprim/sulfamethoxazole

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Trimethoprim/sulfamethoxazole
Trimethoprim and sulfamethoxazole.svg
Trimethoprim (top) and sulfamethoxazole (bottom)
Combination of
Sulfamethoxazole Sulfonamide antibiotic
Trimethoprim Dihydrofolate reductase inhibitor
Clinical data
Trade names Bactrim, Cotrim, Septra, others
Other namesTMP/SMX, cotrimoxazole, Co-trimoxazole (BAN UK)
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		oral, intravenous [2]
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
ChEBI
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Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. [2] It consists of one part trimethoprim to five parts sulfamethoxazole. [7] It is used to treat urinary tract infections, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others. [2] [7] It is used both to treat and prevent pneumocystis pneumonia and toxoplasmosis in people with HIV/AIDS and other causes of immunosuppression. [2] It can be given orally (swallowed by mouth) or intravenous infusion (slowly injected into a vein with an IV). [2]

Contents

Trimethoprim/sulfamethoxazole is on the World Health Organization's List of Essential Medicines. [8] It is available as a generic medication. [7] [9] In 2022, it was the 143rd most commonly prescribed medication in the United States, with more than 3 million prescriptions. [10] [11]

Medical uses

Trimethoprim/sulfamethoxazole generally kills bacteria, [2] by blocking the microorganisms' ability to make and to use folate. [2]

Pneumocystis jirovecii pneumonia

Trimethoprim/sulfamethoxazole (TMP/SMX) is the medicine most commonly used to prevent Pneumocystis jirovecii pneumonia (PCP) [12] People who get Pneumocystis pneumonia have a medical condition that weakens their immune system, like HIV/AIDS, or take medicines (such as corticosteroid, monoclonal antibody and immunosuppressants) that reduce the body's ability to fight bacterial and viral infections. People with HIV/AIDS are less likely to get Pneumocystis pneumonia as a result of antiretroviral therapy (ART). However, Pneumocystis pneumonia is still a substantial public health problem. Most of what is scientifically known about Pneumocystis pneumonia and its treatment comes from studying people with HIV/AIDS. [12]

Susceptibility

Organisms against which trimethoprim/sulfamethoxazole can be effective include: [13] [14]

The only notable nonsusceptible organisms are Pseudomonas aeruginosa , the mycoplasmae [14] and Francisella tularensis (the causative organism of tularaemia). [15] [16]

Pregnancy and breast feeding

Its use during pregnancy is contraindicated, although it has been placed in Australian pregnancy category C. [13] Its use during the first trimester (during organogenesis) and 12 weeks prior to pregnancy has been associated with an increased risk of congenital malformations, especially malformations associated with maternal folic acid deficiency (which is most likely related to the mechanism of action of co-trimoxazole) such as neural tube defects such as spina bifida, cardiovascular malformations (e.g. Ebstein's anomaly), urinary tract defects, oral clefts, and club foot in epidemiological studies. [13] Its use later on during pregnancy also increases the risk of preterm labour (odds ratio: 1.51) and low birth weight (odds ratio: 1.67). [17] [18] Animal studies have yielded similarly discouraging results. [3]

It appears to be safe for use during breastfeeding as long as the baby is healthy. [19]

Babies

Its use in those less than 2 months of age is not recommended due to the risk of adverse side effects. [20]

Adverse effects

Common side effects include nausea, vomiting, rash, and diarrhea. [2] Severe allergic reactions and Clostridioides difficile infection may occasionally occur. [2] Its use in pregnancy is not recommended. [2] [19] It appears to be safe for use during breastfeeding as long as the baby is healthy. [19]

Contraindications

Contraindications include the following: [13] [5]

Interactions

Its use is advised against in people being concomitantly treated with: [13] [3] [5] [6] [21] [22]

Overdose

Likely signs of toxicity include: [3]

  • Nausea
  • Vomiting
  • Dizziness
  • Headache
  • Mental depression
  • Confusion
  • Thrombocytopenia
  • Uremia
  • Bone marrow depression
  • Loss of appetite
  • Colic
  • Drowsiness
  • Unconsciousness

The recommended treatment for overdose includes: [3]

Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim. [3]

Pharmacology

Tetrahydrofolate synthesis pathway THFsynthesispathway.png
Tetrahydrofolate synthesis pathway

The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s. [25] [26] [27] Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately, because they inhibit successive steps in the folate synthesis pathway. They are given in a one-to-five ratio in their tablet formulations so that when they enter the body their concentration in the blood and tissues is roughly one-to-twenty — the exact ratio required for a peak synergistic effect between the two. [14]

Sulfamethoxazole, a sulfonamide, induces its therapeutic effects by interfering with the de novo (that is, from within the cell) synthesis of folate inside microbial organisms such as protozoa, fungi and bacteria. It does this by competing with p-aminobenzoic acid (PABA) in the biosynthesis of dihydrofolate. [14]

Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate. [14]

Tetrahydrofolate is crucial in the synthesis of purines, thymidine, and methionine which are needed for the production of DNA and proteins [28] during bacterial replication.

The effects of trimethoprim causes a backlog of dihydrofolate (DHF) and this backlog can work against the inhibitory effect the drug has on tetrahydrofolate biosynthesis. This is where the sulfamethoxazole comes in; its role is in depleting the excess DHF by preventing it from being synthesised in the first place. [14]

Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed. [29] [30]

Pharmacokinetics of co-trimoxazole [13] [3]
ComponentTmax (h) Vd (L)Protein bindingt1/2 (h)Excretion
Sulfamethoxazole 1-42066%8-10Renal
Trimethoprim 1-413042-45%10Renal

Society and culture

Indications for co-trimoxazole
Indication Flag of the United States.svg
FDA-labelled indication?		 Flag of Australia (converted).svg
TGA-labelled indication?		 Flag of the United Kingdom.svg
MHRA-labelled indication?		Literature support
Acute infective exacerbation of COPD YesNoNoClinical trials are lacking.
Prophylaxis in HIV-infected individualsNoNoNoEffective in one Ugandan study on morbidity, mortality, CD4-cell count, and viral load in HIV infection. [31]
Otitis media Paediatric population onlyNoYesClinical trials have confirmed its efficacy in chronic active otitis media [32] and acute otitis media. [33]
Travellers' diarrhea, treatment & prophylaxisYesNoNoClinical trials have confirmed its efficacy as a treatment for travellers' diarrhea. [34] [35] [36]
Urinary tract infection YesNoYesClinical trials have confirmed its efficacy in this indication. [14]
Bacterial infections
Acne vulgaris NoNoNoAt least one clinical trial supports its use in this indication. [37]
Listeria NoYesNoWell-designed clinical trials are lacking.
Melioidosis NoYesNoClinical trials have confirmed its efficacy, with or without adjunctive doxycycline; although, co-trimoxazole alone seems preferable. [38] [39] [40]
Pertussis (whooping cough)NoNoNoOne cochrane review supports its efficacy in preventing the spread of pertussis. [41]
Shigellosis YesYesNoGenerally accepted treatment for shigellosis. [42] A recent Cochrane review found that while it is an effective treatment for shigellosis it also produces more significant adverse effects than other antibiotic drugs. [43]
Staphylococcus aureus infectionsNoNoNoIn vitro and in vivo activity against both non-resistant and methicillin-resistant Staphylococcus aureus (MRSA) infections. [44] [45] [46] [47] [48] [49] [50]
Tuberculosis NoNoNoIn vitro and in vivo activity against both nonresistant and MDR strains of TB. [51] [52] [53]
Whipple's disease NoNoNoCo-trimoxazole is the recommended standard treatment for whipple's disease in some treatment protocols. [54] [55] [56]
Fungal and protozoal infections
Isosporiasis NoNoNoClinical trials have confirmed its use in this indication. [57]
Malaria NoNoNoClinical trials have confirmed its efficacy in both the treatment and prevention of malaria. [58]
Pneumocystis jirovecii pneumonia YesYesYesIts use as a prophylactic treatment is supported by one clinical trial involving children with acute lymphoblastic leukaemia. [59] Other than this and one other clinical trial into its efficacy as a treatment for pneumocystis pneumonia, [60] data on its use in both the treatment and prevention of pneumocystis pneumonia is significantly lacking.
Toxoplasmosis YesPrevention onlyYesClinical trials have confirmed its prophylactic and therapeutic utility in cases of toxoplasmosis. [61] [62] [63] [64] [65] [66]

Brand names

Trimethoprim/sulfamethoxazole may be abbreviated as SXT, SMZ-TMP, TMP-SMX, TMP-SMZ, or TMP-sulfa.[ citation needed ] The generic British Approved Name (BAN) Co-trimoxazole is used for trimethoprim/sulfamethoxazole manufactured and sold by many different companies. [67]

The following list of brand names is incomplete:

  • Bactrim, Bactrimel (manufactured by Roche and distributed in Europe)
  • Bactrom (Venezuela)
  • Bibactin (manufactured by PPM and distributed in Cambodia and some African countries)
  • Biseptol
  • Sumetrolim
  • Co-trimoxazole (used as generic UK name)
  • Cotrim
  • Deprim (AFT Pharmaceuticals)
  • Diseptyl (Israel)
  • Graprima Forte Kaplet (manufactured by PT Graha Farma and distributed in Indonesia)
  • Infectrin, Bactrim (Brazil)
  • Novo-Trimel [68]
  • Primadex (manufactured by Dexa Medica and distributed in Indonesia)
  • Primotren (Lek in Slovenia and other countries)
  • Resprim
  • Sanprima (manufactured by PT Sanbe Farma and distributed in Indonesia)
  • Septra (Aspen Pharmacare and formerly GlaxoSmithKline)
  • Septram (Panama)
  • Septran (GlaxoSmithKline) [69]
  • Septrin (Spain) [70]
  • Sulfatrim
  • Teva-Trimel
  • Trisul
  • Vactrim (manufactured and distributed in Laos)

Economics

Trimethoprim/sulfamethoxazole is relatively inexpensive as of 2019. [9]

Related Research Articles

<span class="mw-page-title-main">Trimethoprim</span> Antibiotic

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS. It is taken orally.

<i>Staphylococcus aureus</i> Species of gram-positive bacterium

Staphylococcus aureus is a gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive for catalase and nitrate reduction and is a facultative anaerobe, meaning that it can grow without oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA). The bacterium is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

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Methicillin-resistant Staphylococcus aureus (MRSA) is a group of gram-positive bacteria that are genetically distinct from other strains of Staphylococcus aureus. MRSA is responsible for several difficult-to-treat infections in humans. It caused more than 100,000 deaths worldwide attributable to antimicrobial resistance in 2019.

<span class="mw-page-title-main">Linezolid</span> Antibiotic medication

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<span class="mw-page-title-main">Clindamycin</span> Antibiotic

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<span class="mw-page-title-main">Hospital-acquired infection</span> Infection that is acquired in a hospital or other health care facility

A hospital-acquired infection, also known as a nosocomial infection, is an infection that is acquired in a hospital or other healthcare facility. To emphasize both hospital and nonhospital settings, it is sometimes instead called a healthcare-associated infection. Such an infection can be acquired in a hospital, nursing home, rehabilitation facility, outpatient clinic, diagnostic laboratory or other clinical settings. A number of dynamic processes can bring contamination into operating rooms and other areas within nosocomial settings. Infection is spread to the susceptible patient in the clinical setting by various means. Healthcare staff also spread infection, in addition to contaminated equipment, bed linens, or air droplets. The infection can originate from the outside environment, another infected patient, staff that may be infected, or in some cases, the source of the infection cannot be determined. In some cases the microorganism originates from the patient's own skin microbiota, becoming opportunistic after surgery or other procedures that compromise the protective skin barrier. Though the patient may have contracted the infection from their own skin, the infection is still considered nosocomial since it develops in the health care setting. The term nosocomial infection is used when there is a lack of evidence that the infection was present when the patient entered the healthcare setting, thus meaning it was acquired or became problematic post-admission.

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