Trimethoprim Sulfamethoxazole


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Tyler Kemnic


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Meghan Coleman


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Sandeep Sekhon


Updated:
7/24/2019 8:20:53 AM

Indications

Trimethoprim/sulfamethoxazole, also known as co-trimoxazole and can be abbreviated in the following ways: SXT, TMP-SMX, TMP-SMZ, or TMP-Sulfa. It is an antibiotic used to treat and prevent many bacterial infections. In 1974, TMP/SMX healthcare professionals began prescribing the medication, and the drug is now on the list of the World Health Organization's (WHO) essential medicines. This drug is very cost affordable and used for many types of illness.[1][2][3][4]

The FDA-Approved Indications

  • Acute infective exacerbation of chronic bronchitis
  • Otitis media in pediatrics only
  • Travelers diarrhea for treatment and prophylaxis
  • Urinary tract infections
  • Shigellosis
  • Pneumocystis jirovecii pneumonia/Pneumocystis carinii pneumonia (PCP) both prophylactic and treatment
  • Toxoplasmosis both prophylactic and treatment

The Non-FDA Approved Indications

  • Prophylaxis in HIV-infected individuals
  • Acne vulgaris
  • Listeria
  • Melioidosis
  • Pertussis (whooping cough)
  • Staph aureus infections, including methicillin-resistant Staphylococcus aureus (MRSA)
  • Tuberculosis
  • Whipple disease
  • Isosporiasis
  • Malaria
  • Community-acquired pneumonia

Mechanism of Action

Sulfamethoxazole is a sulfonamide and works directly on the synthesis of folate inside microbial organisms. Sulfamethoxazole achieves this directly as a competitor of p-aminobenzoic acid (PABA) during the synthesis of dihydrofolate. Trimethoprim is a direct competitor of the enzyme dihydrofolate reductase, causing its inhibition, which halts the production of tetrahydrofolate to its active form of folate. Tetrahydrofolate is a necessary component for the synthesis of purines required for DNA and protein production. When used alone, the drugs only act in a bacteriostatic manner. However, when used in the combination of sulfamethoxazole-trimethoprim, they block two steps in the bacterial biosynthesis of essential nucleic acids and proteins, thus are bactericidal.

Administration

Sulfamethoxazole/trimethoprim may be administered orally without regard to meals, however, is best taken with at least 8 ounces of water. It also has an intravenous formulation. The choice of oral or intravenously varies both on the type of infection/or preventative desire. It should not be administered intramuscularly. Patients with impaired renal function must have calculated dosing regiments based on renal function as listed below. The two drugs are given in a 1 to 5 ratio as a tablet formulation; this is so when they enter the body, their concentration throughout the blood/tissues is 1 to 20, which is the peak synergistic desired effect ratio of the two drugs in combination.

Bacterial infections

Oral dosage in adults and children weighing 40 kg (88 pounds) or more should have a single tablet of 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 10 to 14 days. Children 2 months and older must have a weight-adjusted dosage.

Treatment of Pneumocystis jirovecii Pneumonia/ Pneumocystis carinii Pneumonia

Adults/children, 2 months of age and older: The dose is also weight adjusted. Usually 75 to 100 mg per kilogram of body weight of sulfamethoxazole and 15 to 20 mg per kilogram body of body weight of trimethoprim each day for 14 to 21 days.

Prevention of Pneumocystis jirovecii pneumonia/ pneumocystis carinii pneumonia

In adults, 800 mg of sulfamethoxazole and 160 mg of trimethoprim is given once a day. In children, 2 months of age and older, dosages are determined by body size.

Traveler's Diarrhea

In adults 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 5 days. For children, 2 months and older use and dosage vary.

Chronic Bronchitis

For acute exacerbations due to strains of Streptococcus pneumoniae or Haemophilus influenzae one tablet of 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 10 to 14 days.

Shigellosis

Enteritis caused by Shigella flexneri and Shigella sonnei: 1 tablet 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 5 days.

Urinary Tract Infections

Pyelonephritis

One tablet 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 14 days

Prostatitis

One tablet 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 14 days or 2 to 3 months if a chronic infection

Acne Vulgaris (Non-FDA Approved)

One tablet 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 18 days

Community-Acquired Pneumonia (Non-FDA Approved)

One tablet 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 10 to 14 days

Renal impairment guidelines are as follows:

  • CrCl greater than 30 mL per minute no dose change
  • CrCl 15 to 30 mL per minute decrease dose by 50%
  • CrCl less than 15 do no use

Use is not recommended in children younger than 2 months of age.

Adverse Effects

The primary adverse effects of trimethoprim/sulfamethoxazole include rash, photosensitivity, as well as folate deficiency.[5][6][7] A list of side effects are as follows:

  • Loss of appetite
  • Nausea/vomiting
  • Painful or swollen tongue
  • Dizziness
  • Tinnitus
  • Fatigue
  • Insomnia

A patient with an unknown sulfa allergy then treated with trimethoprim/sulfamethoxazole may experience anaphylaxis or less serious yet severe symptoms such as hives, itchy eyes, swelling of the mouth and/or throat, and abdominal cramping.

Contraindications

Trimethoprim/Sulfamethoxazole Contraindications

  • Known hypersensitivity to either drug or a past sulfa allergy
  • Pregnancy
  • Liver parenchymal damage, jaundice, and hepatic failure
  • Hematological disorders
  • Renal insufficiency 
  • Neonate less than 6 weeks of age

Trimethoprim/sulfamethoxazole is American pregnancy category D medication. Use during early pregnancy has been related to congenital malformations and maternal folic acid deficiency; this may cause neural tube defects (spina bifida), urinary tract defects, oral clefts, and clubbed feet. Use during late pregnancy has been related to preterm labor. The drug is also excreted in breast milk, and patients that are breastfeeding should not use trimethoprim/sulfamethoxazole during this time. 

Trimethoprim/sulfamethoxazole should not be taken with any of the following:

  • ACE inhibitors: Risk of hyperkalemia 
  • Prilocaine: Risk of methemoglobinemia
  • Antiarrhythmics: Risk of QT prolongation 
  • Dapsone: Increases plasma levels of both drugs
  • Methenamine: Risk of crystalluria
  • Rifampicin: Risk of reducing trimethoprim plasma levels
  • Sulfonylureas 
  • Phenytoin: Increase in the half-life of phenytoin
  • Antifolates: Risk of megaloblastic anemia
  • Lamivudine, zalcitabine, and zidovudine
  • Procainamide and/or amantadine 
  • Clozapine
  • Digoxin: Increase in digoxin levels
  • Diuretics: Risk of thrombocytopenia
  • Ciclosporin: Risk of kidney function decline
  • Spironolactone: Risk of hyperkalemia

Monitoring

When initiating therapy with trimethoprim/sulfamethoxazole, some patients may require a baseline blood urea nitrogen and serum creatinine ratio, frequent complete blood counts (CBC), and electrolyte measurements if renal impairment is known or if taking a drug that has interactions with potassium.

Toxicity

Overdosing on trimethoprim/sulfamethoxazole is possible, and potential signs of toxicity include:

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

If there is suspicion of a patient having trimethoprim/sulfamethazine toxicity, a treatment plan includes the administration of activated charcoal, stomach pumping, and supportive intravenous (IV) and oral fluids. More severe measures of treatment may consist of hemodialysis and alkalize the patient's urine.

Enhancing Healthcare Team Outcomes

Prescribing clinicians including nurse practitioners, primary care providers, and internists who prescribe trimethoprim/sulfamethoxazole should be familiar with ints indications and adverse effects. Also, when a patient receives a prescription of trimethoprim/sulfamethoxazole some patients may need a baseline blood urea nitrogen and serum creatinine ratio, frequent complete blood counts (CBC), and electrolyte measurements if renal impairment is known or if taking a drug that has interactions with potassium.

Pharmacists should be consulted to verify coverage in conjunction with an infectious disease specialist, verify dosing, and perform medication reconciliation, and report any concerns to the rest of the healthcare team. Nurses will administer the drug inpatient, and can also verify that there are no adverse events as a result of therapy with TMP-SMX; reporting any concerns immediately to the prescriber.  In cases of pediatric use or renal impairment, the pharmacist, nursing, and prescriber should coordinate to ensure proper dosing. As with any medication therapy, antimicrobial treatment with TMP-SMX requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Trimethoprim Sulfamethoxazole - Questions

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Trimethoprim/sulfamethoxazole inhibits which of the following?



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A patient has been diagnosed with a urinary tract infection. However, he also has been diagnosed with hypoaldosteronism. Which of the following antibiotics, indicated to treat urinary tract infections, would not be the best option for this patient?



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What is the mechanism by which sulfamethoxazole/trimethoprim works as a combination drug that is superior to either one of the agents were administered alone?



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A woman delivers a premature baby with jaundice. The infant is in the neonatal unit with hyperbilirubinemia. The mother was treated with antibiotics for a urinary tract infection not long before delivery. Which of the following drugs is most likely to cause this condition?



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A male college student is treated at the school infirmary for an upper respiratory infection. He was given sulfamethoxazole-trimethoprim and responded well. Which of the following is involved in the mechanism of action for this drug combination?



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Trimethoprim Sulfamethoxazole - References

References

García-Solache M,Rice LB, The Enterococcus: a Model of Adaptability to Its Environment. Clinical microbiology reviews. 2019 Mar 20;     [PubMed]
Huang L,Chen X,Xu H,Sun L,Li C,Guo W,Xiang L,Luo G,Cui Y,Lu B, Clinical features, identification, antimicrobial resistance patterns of Nocardia species in China: 2009-2017. Diagnostic microbiology and infectious disease. 2018 Dec 29;     [PubMed]
Krooks J,Weatherall A,Markowitz S, Complete Resolution of {i}Mycobacterium marinum{/i} Infection with Clarithromycin and Ethambutol: A Case Report and a Review of the Literature. The Journal of clinical and aesthetic dermatology. 2018 Dec;     [PubMed]
She WH,Chok KSH,Li IWS,Ma KW,Sin SL,Dai WC,Fung JYY,Lo CM, Pneumocystis jirovecii-related spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema in a liver transplant recipient: a case report. BMC infectious diseases. 2019 Jan 18;     [PubMed]
McGee M,Brienesse S,Chong B,Levendel A,Lai K, {i}Tropheryma whipplei{/i} Endocarditis: Case Presentation and Review of the Literature. Open forum infectious diseases. 2019 Jan;     [PubMed]
Hanlon JT,Perera S,Drinka PJ,Crnich CJ,Schweon SJ,Klein-Fedyshin M,Wessel CB,Saracco S,Anderson G,Mulligan M,Nace DA, The IOU Consensus Recommendations for Empirical Therapy of Cystitis in Nursing Home Residents. Journal of the American Geriatrics Society. 2018 Dec 24;     [PubMed]
Gallardo-Cartagena JA,Chiappe-Gonzalez AJ,Astocondor-Salazar LM,Salazar-Mesones BN,Narcizo Susanibar JA,Cucho-Espinoza C,Huaroto-Valdivia LM,Ticona-Chávez ER, [Vibrio cholerae NO-O1/NO-O139 bacteremia in a cirrhotic patient. First case report in Peru and literatura review]. Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru. 2018 Jul-Sep;     [PubMed]

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