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Sulfamethoxazole and Trimethoprim

Pronunciation

(sul fa meth OKS a zole & trye METH oh prim)

Index Terms

  • Co-Trimoxazole
  • Septra
  • SMX-TMP
  • SMZ-TMP
  • Sulfamethoxazole/Trimethoprim
  • Sulfatrim
  • TMP-SMX
  • TMP-SMZ
  • Trimethoprim and Sulfamethoxazole

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: Sulfamethoxazole 80 mg and trimethoprim 16 mg per mL (5 mL, 10 mL, 30 mL)

Suspension, Oral:

Sulfatrim Pediatric: Sulfamethoxazole 200 mg and trimethoprim 40 mg per 5 mL (473 mL) [contains alcohol, usp, fd&c red #40, fd&c yellow #6 (sunset yellow), methylparaben, polysorbate 80, propylene glycol, propylparaben, saccharin sodium; cherry flavor]

Generic: Sulfamethoxazole 200 mg and trimethoprim 40 mg per 5 mL (20 mL, 473 mL)

Tablet, Oral:

Bactrim: Sulfamethoxazole 400 mg and trimethoprim 80 mg [scored; contains sodium benzoate]

Bactrim DS: Sulfamethoxazole 800 mg and trimethoprim 160 mg [scored; contains sodium benzoate]

Generic: Sulfamethoxazole 400 mg and trimethoprim 80 mg, Sulfamethoxazole 800 mg and trimethoprim 160 mg

Brand Names: U.S.

  • Bactrim
  • Bactrim DS
  • Sulfatrim Pediatric

Pharmacologic Category

  • Antibiotic, Miscellaneous
  • Antibiotic, Sulfonamide Derivative

Pharmacology

Sulfamethoxazole interferes with bacterial folic acid synthesis and growth via inhibition of dihydrofolic acid formation from para-aminobenzoic acid; trimethoprim inhibits dihydrofolic acid reduction to tetrahydrofolate resulting in sequential inhibition of enzymes of the folic acid pathway

Absorption

Oral: Rapid; almost completely (90% to 100%)

Distribution

Both SMX and TMP distribute to middle ear fluid, sputum, vaginal fluid; TMP also distributes into bronchial secretions

Vd: TMP:

Newborns: ~2.7 L/kg (range: 1.3 to 4.1 hours) (Springer 1982)

Infants: 1.5 L/kg (Hoppu 1989)

Children 1 to 10 years: 0.86 to 1 L/kg (Hoppu 1987)

Adults: ~1.3 L/kg (Hoppu 1987)

Metabolism

Hepatic, both to multiple metabolites; SMX to hydroxy (via CYP2C9) and acetyl derivatives, and also conjugated with glucuronide; TMP to oxide and hydroxy derivatives; the free forms of both SMX and TMP are therapeutically active

Excretion

Both are excreted in urine as metabolites and unchanged drug

Time to Peak

Serum: Oral: 1 to 4 hours

Half-Life Elimination

TMP: Prolonged in renal failure

Newborns: ~19 hours; range: 11 to 27 hours (Springer 1982)

Infants 2 months to 1 year: ~4.6 hours; range: 3 to 6 hours (Hoppu 1989)

Children 1 to 10 years: 3.7 to 5.5 hours (Hoppu 1987)

Children and Adolescents >10 years: 8.19 hours

Adults: 6 to 11 hours

SMX: 9 to 12 hours, prolonged in renal failure

Protein Binding

SMX: ~70%, TMP: ~44%

Special Populations: Renal Function Impairment

Patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage adjustments.

Special Populations: Elderly

Total body clearance of trimethoprim was 19% lower in elderly patients.

Use: Labeled Indications

Oral: Treatment of urinary tract infections due to Escherichia coli, Klebsiella and Enterobacter sp, Morganella morganii, Proteus mirabilis and Proteus vulgaris; acute otitis media; acute exacerbations of COPD due to susceptible strains of Haemophilus influenzae or Streptococcus pneumoniae; treatment and prophylaxis of Pneumocystis pneumonia (PCP); traveler's diarrhea due to enterotoxigenic E. coli; treatment of Shigellosis caused by Shigella flexneri or Shigella sonnei

IV: Treatment of Pneumocystis pneumonia (PCP); treatment of Shigellosis caused by Shigella flexneri or Shigella sonnei; treatment of severe or complicated UTIs due to E. coli, Klebsiella and Enterobacter spp, M. morganii, P. mirabilis, and P. vulgaris

Off Label Uses

Bite wound infections (animal and human bites)

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), sulfamethoxazole and trimethoprim, in combination with an appropriate agent for anaerobic coverage, is an effective and recommended alternative for the prophylaxis and treatment of animal bite wounds.

Clinical experience suggests the utility of sulfamethoxazole and trimethoprim as an alternative agent for the prophylaxis and treatment of human bite wounds [Harper 2017].

Brain abscess, empyema, and epidural abscess (methicillin-resistant Staphylococcus aureus)

IDSA guidelines cite limited data evaluating the effectiveness of sulfamethoxazole and trimethoprim in the treatment of brain abscess, subdural empyema, and epidural abscess caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the guidelines support the initial use and evaluation of vancomycin treatment; if vancomycin is contraindicated or resistance is expected, use of linezolid or sulfamethoxazole and trimethoprim should be considered as alternative therapy. Sulfamethoxazole and trimethoprim can be given as a single agent or in combination with rifampin.

Cyclosporiasis

Data from a randomized, double-blind, placebo-controlled trial in immunocompetent patients [Hoge 1995 [LOE B]] and a prospective cohort study in patients with HIV [Pape 1994 [LOE C]] support the use of sulfamethoxazole and trimethoprim in the treatment of cyclosporiasis.

Based on the Centers for Disease Control (CDC) recommendations for the treatment for cyclosporiasis, sulfamethoxazole and trimethoprim is the preferred treatment for cyclosporiasis (immunocompetent or HIV-infected patients).

Cystoisosporiasis (Isosporiasis)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, sulfamethoxazole and trimethoprim is an effective and recommended agent in the treatment of or as chronic suppressive therapy (secondary prophylaxis) of Isospora belli infection in adolescent and adult HIV-infected patients.

Based on the Centers for Disease Control (CDC) recommendations for the treatment for cystoisosporiasis, sulfamethoxazole and trimethoprim is the preferred treatment for Cystoisospora belli (Isospora belli) in immunocompetent (when treatment is indicated) or immunosuppressed patients (expert consultation is recommended).

Diabetic foot infection

According to IDSA guidelines, sulfamethoxazole and trimethoprim is a reasonable treatment option for mild diabetic foot infections.

Granuloma inguinale (Donovanosis)

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, sulfamethoxazole and trimethoprim is an effective and recommended alternative agent in the treatment of granuloma inguinale.

Head lice (Pediculosis capitis)

Most sulfamethoxazole and trimethoprim trials for the treatment of head lice studied the drug in addition to standard treatment. There is little evidence to support treatment with sulfamethoxazole and trimethoprim as a single agent for head lice infestation, but it may have some benefit when used as part of combination therapy. Current guidelines do not recommend the use of sulfamethoxazole and trimethoprim for head lice infestation if other options are available.

Melioidosis (Burkholderia pseudomallei) infection

A DHHS Workshop on Treatment of and Postexposure Prophylaxis for Burkholderia pseudomallei and B. mallei infection suggests the use of sulfamethoxazole and trimethoprim as a potential addition to initial intensive therapy (with ceftazidime or a carbapenem) in focal disease of the CNS, prostate, bone, or other deep-seated infection, and as eradication therapy (initiated after completion of initial intensive therapy) [Lipsitz 2012].

Meningitis, bacterial

Based on the Infectious Diseases Society of America (IDSA) guidelines for the management of bacterial meningitis and health care-associated ventriculitis and meningitis, sulfamethoxazole and trimethoprim is an effective and recommended alternative agent for the treatment of meningitis due to MRSA, Listeria monocytogenes, E. coli, and other susceptible Enterobacteriaceae.

Nocardiosis

Data from a limited number of patients studied suggest that sulfamethoxazole and trimethoprim may be beneficial for the treatment of nocardiosis (as monotherapy or combination therapy, depending on severity of infection) [Wang 2015].

Clinical experience also suggests the utility of sulfamethoxazole and trimethoprim in the treatment of nocardiosis [Lerner 1996].

Osteomyelitis

According to IDSA and SIMIT guidelines, sulfamethoxazole and trimethoprim, in combination with rifampin, is a reasonable treatment option for MRSA osteomyelitis.

Peritonitis, spontaneous bacterial (prevention)

Data from controlled trials support use of sulfamethoxazole and trimethoprim as primary long-term prophylaxis in cirrhotic patients with low protein ascites with or without renal or liver impairment, or as secondary long-term prophylaxis in patients who have experienced a prior SBP episode.

According to AASLD and EASL guidelines, long-term prophylaxis with daily sulfamethoxazole and trimethoprim should be considered as secondary prophylaxis in patients who have experienced a prior SBP episode, and as primary prophylaxis in cirrhotic patients with low protein ascites. Increasing bacterial resistance rates to antibiotics used in the treatment and prevention of SBP have been documented; therefore, local epidemiological patterns should be considered, and use of antibiotic prophylaxis should be restricted to patients at high risk of SBP.

Prosthetic joint infection

Data from a limited number of patients in a prospective, consecutive, therapeutic case series with no control group suggest that sulfamethoxazole and trimethoprim may be beneficial for the treatment of prosthetic joint infection [Cordero-Ampuero 2007]. Additional data may be necessary to further define the role of sulfamethoxazole/trimethoprim in the treatment of this condition.

Based on the Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Diagnosis and Management of Prosthetic Joint Infection, sulfamethoxazole and trimethoprim is an effective and recommended agent for chronic oral antimicrobial suppression of Staphylococcal prosthetic joint infection after completion of parenteral therapy.

Q Fever (Coxiella burnetii)

Based on the Centers for Disease Control and Prevention (CDC) Diagnosis and Management of Q Fever guidelines, sulfamethoxazole and trimethoprim given for the treatment of Q Fever (Coxiella burnetii) is effective and recommended in the management of this condition in pregnant women up to 32 weeks (alternative agent in nonpregnant adults).

Septic arthritis (methicillin-resistant Staphylococcus aureus)

Based on the Infectious Diseases Society of America (IDSA) guidelines for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in adults and children, sulfamethoxazole and trimethoprim is an effective and recommended treatment option for septic arthritis without prosthetic material caused by MRSA following initial therapy with an appropriate IV antibiotic.

Skin and soft tissue infections (methicillin-resistant Staphylococcus aureus)

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI) and the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in adults and children, sulfamethoxazole and trimethoprim is an effective and recommended treatment option for mild to moderate skin and soft tissue infections caused by MRSA.

Stenotrophomonas maltophilia infections

Data from a limited number of patients studied suggest that sulfamethoxazole and trimethoprim may be beneficial for the treatment of Stenotrophomonas maltophilia infections [Wang 2014]. Additional data may be necessary to further define the role of sulfamethoxazole and trimethoprim in this condition.

Clinical experience also suggests the utility of sulfamethoxazole and trimethoprim in the treatment of Stenotrophomonas maltophilia [Looney 2009].

Toxoplasma gondii encephalitis (prophylaxis/treatment/chronic maintenance) in HIV-infected patients (adolescents and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, sulfamethoxazole and trimethoprim is an effective and recommended agent for primary prophylaxis of Toxoplasma gondii encephalitis and is an effective and recommended alternative agent for the treatment of or as chronic maintenance therapy of Toxoplasma gondii encephalitis in adolescent and adult HIV-infected patients.

Contraindications

Hypersensitivity to any sulfa drug, trimethoprim, or any component of the formulation; history of drug induced-immune thrombocytopenia with use of sulfonamides or trimethoprim; megaloblastic anemia due to folate deficiency; infants <2 months (manufacturer's labeling), infants <4 weeks (CDC 2009); marked hepatic damage or severe renal disease (if patient not monitored); concomitant administration with dofetilide

Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail.

Canadian labeling: Additional contraindications (not in US labeling): Blood dyscrasias; pregnancy; breastfeeding.

Dosing: Adult

Note: Weight-based dosing recommendations are based on the trimethoprim (TMP) component. Each double-strength tablet contains TMP 160 mg and sulfamethoxazole (SMX) 800 mg. Each single-strength tablet contains TMP 80 mg and SMX 400 mg. The undiluted IV solution contains TMP 16 mg per mL and SMX 80 mg per mL. IV solutions must be diluted in D5W prior to use. Diluted IV solutions have limited stability and can precipitate unpredictably; refer to a detailed IV compatibility reference.

General dosing guidelines:

Oral: 1 to 2 double-strength tablets every 12 to 24 hours. Note: Serum creatinine and potassium concentrations should be monitored in outpatients receiving high-dose therapy (>5 mg/kg TMP component/day) (Gentry 2013)

IV: 8 to 20 mg (TMP component)/kg/day divided every 6 to 12 hours

Bite wound infections, prophylaxis or treatment (animal, human; alternative agent) (off-label use): Oral: One double-strength tablet twice daily; in combination with an appropriate agent for anaerobic coverage. Duration of treatment for prophylaxis is 3 to 5 days; duration of treatment for established infection varies based on patient-specific factors (Harper 2017; IDSA [Stevens 2014]).

Brain abscess, empyema, and epidural abscess (alternative agent for MRSA) (off-label use): IV: 5 mg (TMP component)/kg/dose every 8 to 12 hours (IDSA [Liu 2011])

Chronic obstructive pulmonary disease, acute exacerbations; uncomplicated (alternative agent; outpatient therapy): Oral: One double-strength tablet every 12 hours for 5 to 7 days (Bartlett 2017; GOLD 2017; Snow 2001)

Diabetic foot infection, mild (MRSA) (off-label use): Oral: Two double-strength tablets twice daily, usually for 1 to 2 weeks (IDSA [Lipsky 2012]; Lipsky 2004). Note: When used as empiric therapy, must be used in combination with other appropriate agents. Some experts also use this agent for selected moderate infections (Lipsky 2012).

Diarrhea, infectious:

Cyclosporiasis (off-label use): Oral:

Immunocompromised (AIDS-associated): Limited data available: One double-strength tablet twice daily for 14 days, followed by secondary prophylaxis with one double-strength tablet 3 times weekly (Pape 1994; Weller 2017).

Immunocompetent: One double-strength tablet twice daily for 7 to 10 days (CDC 2017; Hoge 1995)

Cystoisosporiasis (isosporiasis) (off-label use):

Immunocompromised (AIDS-associated): Oral, IV: 160 mg (TMP component) twice daily for 7 to 10 days; if symptoms worsen or persist, may increase dose to 160 mg (TMP component) 4 times daily and/or prolong duration to 21 to 28 days. In patients with CD4 <200 cells/mm3, follow treatment with secondary prophylaxis of one double-strength tablet orally 3 times weekly (HHS [OI adult 2017]).

Immunocompetent (usually self-limited; treatment not always indicated): Oral: One double-strength tablet twice daily for 7 to 10 days (CDC 2017)

Shigellosis (widespread resistance [alternative agent if susceptibility is documented]): Oral: One double strength tablet twice daily for 5 to 7 days (Agha 2017)

Granuloma inguinale (Donovanosis) (alternative agent) (off-label use): Oral: One double-strength tablet every 12 hours for at least 3 weeks and until lesions have healed (CDC [Workowski 2015]). Note: If symptoms do not improve within the first few days of therapy, another agent (eg, aminoglycoside) can be added (CDC [Workowski 2015]).

Melioidosis (Burkholderia pseudomallei) (off-label use):

Initial intensive therapy (as a potential add-on to primary therapy [ceftazidime or a carbapenem] in focal disease of the CNS, prostate, bone, or other deep-seated infection) (Cheng 2009; Lipsitz 2012): Oral, IV:

40 to 60 kg: 240 mg (TMP component) twice daily

>60 kg: 320 mg (TMP component) twice daily

Eradication therapy (begin after completion of initial intensive therapy) (Cheng 2009; Lipsitz 2012): Oral:

40 to 60 kg: 240 mg (TMP component) twice daily

>60 kg: 320 mg (TMP component) twice daily

Meningitis, bacterial (alternative agent for MRSA, L. monocytogenes, E. coli, and other Enterobacteriaceae) (off-label use): IV: 5 mg (TMP component)/kg/dose every 6 to 12 hours (IDSA [Tunkel 2004; Tunkel 2017])

Alternative dosing for MRSA meningitis: 5 mg (TMP component)/kg/dose every 8 to 12 hours (IDSA [Liu 2011])

Nocardiosis (off-label use): Limited data available to guide treatment. Due to concerns for resistance, susceptibility testing should be performed on isolates (CDC 2017)

Cutaneous infections (superficial; no other organ involvement): Oral: 5 to 10 mg (TMP component)/kg/day in 2 divided doses (Spelman 2017)

Pulmonary infection (mild to moderate) (Spelman 2017):

Immunocompetent patients: Oral: 5 to 10 mg (TMP component)/kg/day in 2 divided doses

Immunocompromised patients: IV: 15 mg (TMP component)/kg/day in 3 to 4 divided doses

Pulmonary infection (severe), CNS, disseminated, or multi-site infection: IV: 15 mg (TMP component)/kg/day in 3 to 4 divided doses (Spelman 2017). Note: When used as empiric therapy, must be used in combination with 1 to 2 additional agents. Consult an infectious diseases specialist for specific treatment recommendations.

Duration: Prolonged treatment is required (range: 3 months to ≥1 year [combined parenteral/oral therapy]) (Spelman 2017)

Osteomyelitis due to MRSA (alternative agent; off-label use): Oral, IV: 4 mg (TMP component)/kg/dose every 12 hours with rifampin (Lalani 2017)

Peritonitis, spontaneous bacterial (prevention) (off-label use):

High-risk patients (eg, hospitalized patients with Child-Pugh class B or C cirrhosis and active GI bleeding): Oral: One double-strength tablet twice daily (Runyon 2017)

Long-term secondary SBP prophylaxis: Oral: One double-strength tablet once daily (Runyon 2017)

Pneumocystis pneumonia:

Prophylaxis, primary and secondary (off-label dose):

HIV-infected: Oral: One double-strength tablet once daily or one single-strength tablet once daily (preferred regimens) or one double-strength tablet three times weekly (alternative regimen). Note: In patients also requiring prophylaxis for toxoplasmosis, one double-strength tablet once daily should be used (HHS [OI adult 2017]).

Duration in HIV-infected patients receiving ART: Continue until undetectable viral load and CD4 count >200 cells/mm3 for >3 months (HHS [Adult OI 2017]); some experts discontinue primary prophylaxis in patients with CD4 counts between 100 and 200 cells/mm3 who are receiving ART and have had an undetectable viral load for ≥3 to 6 months (HHS [OI adult 2017]; COHERE 2010) or ≥12 months (Sax 2017).

Immunocompromised host, HIV-uninfected (eg, transplant recipients, cancer-related, hematopoietic stem cell transplant [HCT]) (off-label dose): Oral: One double-strength tablet once daily or one single-strength tablet once daily (preferred regimens); alternatively one double strength tablet three times weekly (Fishman 2001; Montoya 2001; Tomblyn 2009)

Duration after solid organ transplantation (except lung): ≥6 to 12 months and during periods of increased immunosuppression (eg, treatment for acute rejection) (Alexander 2017; Martin 2013)

Duration after lung transplantation: Lifelong therapy should be considered (Palmer 2017; Martin 2013)

Duration for cancer-related (including HSCT) high risk for PCP infection: Based on expert opinion, continue until risk factor(s) for PCP infection are no longer present (Neumann 2013, Thomas 2017). Consult other specialized databases for more detailed information.

Treatment (off-label dose; HHS [OI adult 2017]; ATS [Limper 2011]; Thomas 2017): Note: Secondary prophylaxis should be initiated immediately upon completion of therapy.

Moderate to severe infection: IV: 15 to 20 mg (TMP component)/kg/day in 3 or 4 divided doses for 21 days; may switch to oral therapy after clinical improvement. Note: Patients with moderate or severe infection (PaO2 <70 mm Hg at room air or alveolar-arterial oxygen gradient ≥35 mm Hg) should receive adjunctive glucocorticoids.

Mild to moderate infection: Oral: 15 to 20 mg (TMP component)/kg/day in 3 divided doses for 21 days or two double-strength tablets three times daily.

Prosthetic joint infection (off-label use): Oral:

One-stage (direct exchange) or debridement and retention of the prosthesis, subsequent therapy after completion of pathogen-specific IV therapy (staphylococcal) (alternative agent): One double-strength tablet twice daily in combination with rifampin (IDSA [Osmon 2013])

Chronic suppressive therapy of retained infected joint (MRSA and Enterobacteriaceae infections): One double-strength tablet twice daily (IDSA [Osmon 2013])

Q fever (C. burnetii) (preferred agent for pregnant women ≤32 weeks of gestation; alternative agent for non-pregnant adults) (off-label use): Oral: Acute illness: One double strength tablet twice daily during pregnancy but not beyond 32 weeks' gestation; administer with folic acid supplementation. Note: Discontinue therapy for the final 8 weeks of pregnancy due to hyperbilirubinemia risk (CDC 2013).

Septic arthritis (without prosthetic material) due to MRSA (alternative agent following initial IV therapy with an appropriate antibiotic) (off-label use): Oral: Two double-strength tablets twice daily or 4 mg (TMP component)/kg/dose twice daily (maximum: 320 mg (TMP component)/dose) for completion of 3 to 4 week total treatment course (IV and oral) (Goldenberg 2017; IDSA [Liu 2011])

Skin/soft tissue infection, mild to moderate (outpatient treatment; empiric coverage of MRSA) (off-label use): Oral: One to two double-strength tablets twice daily for 5 to 10 days (IDSA [Liu 2011; Stevens 2014]). Note: For empiric therapy of non-purulent cellulitis, an additional agent (eg, amoxicillin, cephalexin) for beta-hemolytic streptococci coverage is needed (IDSA [Liu 2011])

Stenotrophomonas maltophilia infections (hospital-acquired pneumonia [HAP], ventilator-associated pneumonia [VAP], bacteremia, or other sites) (off-label use): IV: 15 mg (TMP component)/kg/day in 3 or 4 divided doses. Additional data may be necessary to further define the role of sulfamethoxazole/trimethoprim in this condition (Lewis 2017; Looney 2009)

Toxoplasma gondii encephalitis (AIDS-associated) (off-label use):

Primary prophylaxis: Oral: One double-strength tablet once daily (preferred) or one double-strength tablet 3 times weekly or one single-strength tablet once daily; primary prophylaxis is indicated for Toxoplasma IgG-positive patients with CD4 count <100 cells/mm3. Continue primary prophylaxis following initiation of ART until CD4 count >200 cells/mm3 for >3 months; some experts discontinue primary prophylaxis in patients with a CD4 count between 100 to 200 cells/mm3 who are receiving ART and have had an undetectable viral load for ≥3 to 6 months (HHS [OI adult 2017]).

Treatment (alternative agent): Oral, IV: 10 mg (TMP component)/kg/day in 2 divided doses for at least 6 weeks; longer duration may be needed if clinical or radiologic disease is extensive or response is incomplete at 6 weeks (HHS [OI adult 2017]).

Secondary prophylaxis (chronic maintenance therapy; alternative agent): Oral: One double-strength tablet twice daily or, alternatively, one double-strength tablet once daily (lower dose may be associated with increased relapse risk). Continue following initiation of ART until CD4 count >200 cells/mm3 for >6 months (HHS [OI adult 2017]).

Urinary tract infection (off-label dose):

Cystitis, acute uncomplicated (empiric use [avoid if resistance prevalence is known to exceed 20% or if used for UTI in previous 3 months] or targeted therapy [if the isolate is known to be susceptible]): Oral: One double-strength tablet twice daily for 3 days (IDSA [Gupta 2011])

Pyelonephritis, acute uncomplicated (outpatient targeted therapy [if the isolate is known to be susceptible]): Oral: One double-strength tablet twice daily for 14 days (IDSA [Gupta 2011]); for women who have a rapid response to treatment, some experts treat for 7 to 10 days (Hooton 2017)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Weight-based dosing recommendations are based on the trimethoprim (TMP) component. Each double-strength tablet contains TMP 160 mg and sulfamethoxazole (SMX) 800 mg. Each single-strength tablet contains TMP 80 mg and SMX 400 mg. The undiluted IV solution contains TMP 16 mg per mL and SMX 80 mg per mL. IV solutions must be diluted in D5W prior to use. Diluted IV solutions have limited stability and can precipitate unpredictably; refer to a detailed IV compatibility reference.

General dosing guidelines: Infants ≥2 months of age, Children, and Adolescents: Oral, IV: 6 to 12 mg TMP/kg/day in divided doses every 12 hours; maximum single dose: 160 mg TMP/dose (Red Book [AAP 2015])

Indication-specific dosing:

Diarrhea, infectious:

Cyclosporiasis (off-label use): Limited data available: Infants ≥2 months of age, Children, and Adolescents: Immunocompetent patients: Oral: 8 to 10 mg TMP/kg/day in divided doses twice daily for 7 to 10 days; maximum single dose: 160 mg TMP (Red Book [AAP 2015])

Cystoisosporiasis (isosporiasis) (AIDS-associated) (off-label use): Adolescents: Refer to adult dosing.

Shigellosis: Infants ≥2 months of age, Children, and Adolescents: Note: Due to reported widespread resistance, empiric therapy with sulfamethoxazole and trimethoprim is not recommended (CDC-NARMS 2010; WHO 2005).

Oral:

Manufacturer's labeling: 8 mg TMP/kg/day in divided doses every 12 hours for 5 days; maximum single dose: 160 mg TMP

Alternate recommendations (off-label dose): IDSA recommendations for infectious diarrhea: 10 mg TMP/kg/day in divided doses every 12 hours for 3 days (for immunocompetent patients) or 7 to 10 days (for immunocompromised patients); maximum single dose: 160 mg TMP (Guerrant 2001)

IV: 8 to 10 mg TMP/kg/day in divided doses every 6, 8, or 12 hours for 5 days

Otitis media, acute: Infants ≥2 months of age, Children, and Adolescents: Oral: 6 to 10 mg TMP/kg/day in divided doses every 12 hours for 10 days. Note: Due to resistance of S. pneumoniae, should not be used in patients that fail first-line amoxicillin therapy (AAP [Lieberthal 2013]).

Pneumocystis pneumonia (PCP) (HIV-exposed/-positive) (off-label dose):

Prophylaxis:

Infants ≥2 months of age and Children: Initial: IV: 15 to 20 mg TMP/kg/day in divided doses every 6 hours for 21 days; as acute pneumonitis subsides in patients with mild to moderate disease and no malabsorption issues nor diarrhea, may transition to oral therapy of same daily dose (15 to 20 mg/kg/day TMP) administered in divided doses 3 or 4 times daily (HHS [OI pediatric 2016])

Adolescents: Refer to adult dosing.

Treatment:

Infants ≥2 months of age and Children: Initial: IV: 15 to 20 mg TMP/kg/day in divided doses every 6 hours for 21 days; as acute pneumonitis subsides in patients with mild to moderate disease and no malabsorption issues nor diarrhea, may transition to oral therapy of same daily dose (15 to 20 mg/kg/day TMP) administered in divided doses 3 or 4 times daily (HHS [OI pediatric 2016])

Adolescents: Refer to adult dosing.

Q fever (C. burnetii); mild infection (doxycycline therapeutic failure) (off-label use): Oral: Acute illness: Limited data available; base dose on severity of illness: Children <8 years of age: 8 to 10 mg TMP/kg/day in divided doses twice daily for 14 days; a wider dose range of 4 to 20 mg TMP/kg/day divided twice daily has been suggested to address varying degrees of severity; however, reported pediatric efficacy experience (eg, case series) are lacking; monitor patients receiving doses at the high and low end of the range closely for efficacy and possible adverse effects (Bradley 2017; CDC 2013)

Skin/soft tissue infection, mild to moderate (due to MRSA; off-label use): Infants ≥2 months of age, Children, and Adolescents: Oral: 8 to 12 mg TMP/kg/day in divided doses every 12 hours (IDSA [Liu 2011]; alternatively, use of 20 mg TMP/kg/day in divided doses every 6 hours has been reported (Norrby-Teglund 2008). Note: If beta-hemolytic Streptococcus spp are also suspected, a beta-lactam antibiotic should be added to the regimen (IDSA [Liu 2011]).

Toxoplasma gondii encephalitis (HIV-exposed/-infected patients) (off-label use):

Primary prophylaxis:

Infants ≥2 months of age and Children: Oral: 150 mg TMP/m2/day for 3 to 7 days of every week; total daily dose may be given in divided doses every 12 hours for 3 consecutive or alternating days, in divided doses every 12 hours every day or as a single daily dose for 3 consecutive days (HHS [OI pediatric 2016])

Adolescents: Oral: Refer to adult dosing.

Treatment (alternative agent): Adolescents: Oral, IV: Refer to adult dosing.

Secondary prophylaxis (chronic maintenance therapy; alternative agent):

Infants ≥1 month of age and Children: 150 mg TMP/m2/day once daily (HHS [OI pediatric 2016])

Adolescents: Oral: Refer to adult dosing.

Urinary tract infection (off-label dose):

Treatment:

Oral:

Infants and Children 2 to 24 months: 6 to 12 mg TMP/kg/day in divided doses every 12 hours for 7 to 14 days (AAP 2011)

Children >24 months of age and Adolescents: 8 mg TMP/kg/day in divided doses every 12 hours for 3 days; longer duration may be required in some patients; maximum single dose: 160 mg TMP

IV: Infants ≥2 months of age, Children, and Adolescents: 8 to 10 mg TMP/kg/day in divided doses every 6, 8, or 12 hours for up to 14 days with serious infections

Prophylaxis: Infants ≥2 months of age, Children, and Adolescents: Oral: 2 mg TMP/kg/dose once daily (Mattoo 2007; Red Book 2012)

Dosing: Renal Impairment

Adults:

Manufacturer's labeling: Oral, IV:

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl 15 to 30 mL/minute: Administer 50% of recommended dose.

CrCl <15 mL/minute: Use is not recommended and is contraindicated per the manufacturer's labeling in severe renal disease if renal function cannot be monitored.

Alternate recommendations:

Golightly 2013:

Oral: Note: The following dosage adjustments are based on a usual maintenance dose of 1 double-strength tablet every 12 hours.

GFR 10 to 50 mL/minute: One double-strength tablet once, followed by 1 single-strength tablet every 12 hours.

GFR <10 mL/minute: Avoid use; if necessary, 1 double-strength tablet once, followed by 1 single-strength tablet every 24 hours.

Hemodialysis: One double-strength tablet once, followed by 1 single-strength tablet every 24 hours (dose after hemodialysis on dialysis days)

IV: Note: The following dosage adjustments are based on a usual maintenance dose of 4 to 5 mg TMP/kg every 6 hours.

GFR 10 to 50 mL/minute: 4 to 5 mg TMP/kg every 12 hours.

GFR <10 mL/minute: Avoid use; if necessary, 2.5 to 5 mg TMP/kg every 24 hours.

Hemodialysis: 2.5 to 5 mg TMP/kg every 24 hours (dose after hemodialysis on dialysis days)

HHS (OI adult 2016) Pneumocystis pneumonia (PCP), treatment: Note: Renal function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes.

Oral: Note: The following dosage adjustments are based on a usual maintenance dose of 2 double-strength tablets every 8 hours.

CrCl 10 to 30 mL/minute: Two double-strength tablets every 12 hours

CrCl <10 mL/minute: One double-strength tablet every 12 hours or 2 double-strength tablets every 24 hours

Hemodialysis: 2 double-strength tablets once daily (dose after hemodialysis on dialysis days); consider therapeutic drug monitoring to optimize therapy

IV: Note: The following dosage adjustments are based on a usual maintenance dose of 5 mg TMP/kg every 8 hours.

CrCl 10 to 30 mL/minute: 5 mg TMP/kg every 12 hours

CrCl <10 mL/minute: 5 mg TMP/kg every 24 hours

Hemodialysis: 5 mg TMP/kg once daily (dose after hemodialysis on dialysis days); consider therapeutic drug monitoring to optimize therapy

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH/CVVHD/CVVHDF: Oral, IV: 2.5 to 7.5 mg/kg of TMP every 12 hours. Note: Dosing regimen dependent on clinical indication. Critically ill patients with P. jirovecii pneumonia receiving CVVHDF may require up to 10 mg/kg every 12 hours (Heintz 2009).

Pediatric:

Manufacturer's labeling: Infants ≥2 months of age, Children, and Adolescents: Oral, IV:

CrCl >30 mL/minute: No dosage adjustment necessary

CrCl 15 to 30 mL/minute: Administer 50% of recommended dose

CrCl <15 mL/minute: Use is not recommended and is contraindicated per the manufacturer's labeling in severe renal disease if renal function cannot be monitored.

Alternate recommendations:

Children and Adolescents (Veltri 2004): Oral, IV: Note: Renally adjusted dose recommendations are based on doses of 3 to 5 mg/kg/dose every 12 hours.

CrCl 10 to 50 mL/minute/1.73 m2: 3 to 5 mg TMP/kg/dose every 18 hours

CrCl <10 mL/minute/1.73 m2: 3 to 5 mg TMP/kg/dose every 24 hours

Hemodialysis: 3 to 5 mg TMP/kg/dose every 24 hours; administer 2.5 mg TMP/kg/dose after each dialysis session

CRRT (CAVH/CVVH/CAVHD/CVVHD):

Combined dialysis flow + ultrafiltration rate <1,500 mL/m2/hour: 3 to 5 mg TMP/kg/dose every 18 hours

Combined dialysis flow + ultrafiltration rate ≥1,500 mL/m2/hour: 4 to 5 mg TMP/kg/dose every 18 hours

Pneumocystis pneumonia (PCP), treatment: Oral, IV:

Children (Veltri 2004): Note: Renally adjusted dose recommendations are based on doses of 5 mg/kg/dose every 6 hours.

CrCl 10 to 50 mL/minute/1.73 m2: 5 mg TMP/kg/dose every 8 hours

CrCl <10 mL/minute/1.73 m2: 5 mg TMP/kg/dose every 12 hours

Hemodialysis: 5 mg TMP/kg/dose every 12 hours; administer 2.5 mg TMP/kg/dose after each dialysis session

CRRT: CAVH/CVVH/CAVHD/CVVHD: 5 mg TMP/kg/dose every 8 hours

Adolescents: Refer to adult dosing.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in manufacturer’s labeling. Use with caution; use is contraindicated in cases of marked hepatic damage.

Reconstitution

IV: Must dilute well in D5W prior to administration (ie, 1:15 to 1:25, which equates to 5 mL of drug solution diluted in 75-125 mL base solution)

Administration

IV: Infuse diluted solution over 60-90 minutes; not for IM injection

Oral: Administer without regard to meals. Administer with at least 8 ounces of water.

Dietary Considerations

Should be taken with 8 oz of water. May be taken without regard to meals.

Storage

Injection: Store at room temperature; do not refrigerate. Less soluble in more alkaline pH. Protect from light. Solution must be diluted prior to administration. Following dilution, store at room temperature; do not refrigerate. Manufacturer recommended dilutions and stability of parenteral admixture at room temperature (25°C):

5 mL/125 mL D5W; stable for 6 hours.

5 mL/100 mL D5W; stable for 4 hours.

5 mL/75 mL D5W; stable for 2 hours.

Studies have also confirmed limited stability in NS; detailed references should be consulted.

Suspension, tablet: Store at controlled room temperature of 15°C to 25°C (59°F to 77°F). Protect from light.

Drug Interactions

Amantadine: Trimethoprim may enhance the adverse/toxic effect of Amantadine. Specifically, the risk of myoclonus and/or delirium may be increased. Amantadine may increase the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Amantadine. Monitor therapy

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Amodiaquine: Trimethoprim may enhance the neutropenic effect of Amodiaquine. Trimethoprim may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Angiotensin II Receptor Blockers: Trimethoprim may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Trimethoprim may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

AzaTHIOprine: Sulfamethoxazole may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

AzaTHIOprine: Trimethoprim may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Benznidazole: May enhance the adverse/toxic effect of Products Containing Propylene Glycol. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

Chloroprocaine: May diminish the therapeutic effect of Sulfonamide Antibiotics. Management: Avoid concurrent use of chloroprocaine and systemic sulfonamide-based antimicrobials whenever possible. Consider therapy modification

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

CycloSPORINE (Systemic): Sulfonamide Antibiotics may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Sulfonamide Antibiotics may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2C8 Substrates (High risk with Inhibitors): CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates (High risk with Inhibitors). Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Consider therapy modification

CYP2C9 Substrates (High risk with Inhibitors): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapsone (Systemic): Trimethoprim may increase the serum concentration of Dapsone (Systemic). Dapsone (Systemic) may increase the serum concentration of Trimethoprim. Monitor therapy

Dapsone (Topical): Trimethoprim may enhance the adverse/toxic effect of Dapsone (Topical). More specifically, trimethoprim may increase the risk for hemolysis Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Digoxin: Trimethoprim may increase the serum concentration of Digoxin. Monitor therapy

Dofetilide: Trimethoprim may increase the serum concentration of Dofetilide. Avoid combination

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: Trimethoprim may enhance the hyperkalemic effect of Eplerenone. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Fosphenytoin. Management: Consider alternatives to this combination when possible, to avoid potential decreased trimethoprim efficacy and increased phenytoin concentrations/effects. Monitor patients receiving this combination closely for both of these possible effects. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

LamiVUDine: Trimethoprim may increase the serum concentration of LamiVUDine. Monitor therapy

Leucovorin Calcium-Levoleucovorin: May diminish the therapeutic effect of Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with trimethoprim (plus sulfamethoxazole) for Pneumocystis jirovecii pneumonia. If trimethoprim is used for another indication, monitor closely for reduced efficacy. Avoid combination

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Memantine: Trimethoprim may enhance the adverse/toxic effect of Memantine. Specifically, the risk of myoclonus and/or delirium may be increased. Trimethoprim may increase the serum concentration of Memantine. Memantine may increase the serum concentration of Trimethoprim. Monitor therapy

Mercaptopurine: Sulfamethoxazole may enhance the myelosuppressive effect of Mercaptopurine. Monitor therapy

Mercaptopurine: Trimethoprim may enhance the myelosuppressive effect of Mercaptopurine. Monitor therapy

MetFORMIN: Trimethoprim may increase the serum concentration of MetFORMIN. Monitor therapy

Methenamine: May enhance the adverse/toxic effect of Sulfonamide Antibiotics. Specifically, the combination may result in the formation of an insoluble precipitate in the urine. Avoid combination

Methotrexate: Trimethoprim may enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (e.g., bone marrow suppression). Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Phenytoin: Trimethoprim may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Trimethoprim. Management: Consider alternatives to this combination when possible, to avoid potential decreased trimethoprim efficacy and increased phenytoin concentrations/effects. Monitor patients receiving this combination closely for both of these possible effects. Consider therapy modification

Phenytoin: Sulfamethoxazole may increase the serum concentration of Phenytoin. Consider therapy modification

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Potassium P-Aminobenzoate: May diminish the therapeutic effect of Sulfonamide Antibiotics. Avoid combination

PRALAtrexate: Trimethoprim may increase the serum concentration of PRALAtrexate. More specifically, trimethoprim may decrease excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum level and/or possible toxicity with concomitant use of trimethoprim. Monitor for decreased pralatrexate levels with discontinuation of trimethoprim. Monitor therapy

PRALAtrexate: Sulfamethoxazole may increase the serum concentration of PRALAtrexate. More specifically, sulfamethoxazole may decrease excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum level and/or possible toxicity with concomitant use of sulfamethoxazole. Monitor for decreased pralatrexate levels with discontinuation of sulfamethoxazole. Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Procainamide: Trimethoprim may increase serum concentrations of the active metabolite(s) of Procainamide. Trimethoprim may increase the serum concentration of Procainamide. Consider therapy modification

Procaine: May diminish the therapeutic effect of Sulfonamide Antibiotics. Avoid combination

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Repaglinide: Trimethoprim may decrease the metabolism of Repaglinide. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Selexipag. Management: If initiating selexipag in a patient on a moderate CYP2C8 inhibitor, consider a less frequent dosing regimen (ie, once daily). If initiating a moderate CYP2C8 inhibitor in a patient on selexipag, consider a selexipag dose reduction. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Spironolactone: Trimethoprim may enhance the hyperkalemic effect of Spironolactone. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Sulfonylureas: Sulfonamide Antibiotics may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Thiazolidinediones: Trimethoprim may decrease the metabolism of Thiazolidinediones. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Varenicline: Trimethoprim may increase the serum concentration of Varenicline. Management: Monitor for increased varenicline adverse effects with concomitant use of trimethoprim, particularly in patients with severe renal impairment. International product labeling recommendations vary. Consult appropriate labeling. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Sulfonamide Antibiotics may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Test Interactions

Increased creatinine (Jaffé alkaline picrate reaction); increased serum methotrexate by dihydrofolate reductase method

Adverse Reactions

Frequency not defined:

Cardiovascular: Allergic myocarditis, periarteritis nodosa (rare)

Central nervous system: Apathy, aseptic meningitis, ataxia, chills, depression, fatigue, hallucination, headache, insomnia, nervousness, peripheral neuritis, seizure, vertigo

Dermatologic: Erythema multiforme (rare), exfoliative dermatitis (rare), pruritus, skin photosensitivity, skin rash, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare), urticaria

Endocrine & metabolic: Hyperkalemia (generally at high dosages), hypoglycemia (rare), hyponatremia

Gastrointestinal: Abdominal pain, anorexia, diarrhea, glottis edema, kernicterus (in neonates), nausea, pancreatitis, pseudomembranous colitis, stomatitis, vomiting

Genitourinary: Crystalluria, diuresis (rare), nephrotoxicity (in association with cyclosporine), toxic nephrosis (with anuria and oliguria)

Hematologic & oncologic: Agranulocytosis, anaphylactoid purpura (IgA vasculitis; rare), aplastic anemia, eosinophilia, hemolysis (with G6PD deficiency), hemolytic anemia, hypoprothrombinemia, leukopenia, megaloblastic anemia, methemoglobinemia, neutropenia, thrombocytopenia

Hepatic: Cholestatic jaundice, hepatotoxicity (including hepatitis, cholestasis, and hepatic necrosis), hyperbilirubinemia, increased transaminases

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction, serum sickness

Neuromuscular & skeletal: Arthralgia, myalgia, rhabdomyolysis (mainly in AIDS patients), systemic lupus erythematosus (rare), weakness

Ophthalmic: Conjunctival injection, injected sclera

Otic: Tinnitus

Renal: Increased blood urea nitrogen, increased serum creatinine, interstitial nephritis, renal failure

Respiratory: Cough, dyspnea, pulmonary infiltrates

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Dysgeusia (Syed 2016), immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura), prolonged Q-T interval on ECG, thrombotic thrombocytopenic purpura

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: Fatalities associated with severe reactions including agranulocytosis, aplastic anemia, and other blood dyscrasias have occurred; discontinue use at first sign of rash or signs of serious adverse reactions.

• Dermatologic reactions: Fatalities associated with severe reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred; discontinue use at first sign of rash.

• Hepatic necrosis: Fatalities associated with hepatic necrosis have occurred; discontinue use at first sign of rash or signs of serious adverse reactions.

• Hyperkalemia: May cause hyperkalemia; potential risk factors for trimethoprim-induced hyperkalemia include high dosage (20 mg/kg/day of trimethoprim), renal impairment, older age, hypoaldosteronism, and concomitant use of medications causing or exacerbating hyperkalemia (Perazella 2000).

• Hypoglycemia: May cause hypoglycemia, particularly in malnourished, or patients with renal or hepatic impairment.

• Hyponatremia: Severe and symptomatic hyponatremia may occur, particularly in patients treated for Pneumocystis jirovecii pneumonia (PCP).

• Sulfonamide (“sulfa”) allergy: Traditionally, concerns for cross-reactivity have extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur, or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides and antibiotic sulfonamides. A nonantibiotic sulfonamide compound which contains the arylamine structure and therefore may cross-react with antibiotic sulfonamides is sulfasalazine (Zawodniak 2010). T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

• Thrombocytopenia: Immune mediated thrombocytopenia may occur. Severe cases which may be life-threatening or fatal have been reported. Thrombocytopenia usually resolves within 1 week following discontinuation of therapy.

Disease-related concerns:

• Asthma/allergies: Use with caution in patients with allergies or asthma.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended. Maintain adequate hydration to prevent crystalluria.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Leucovorin: Avoid concomitant use when treating Pneumocystis jirovecii pneumonia (PCP) in HIV patients; may increase risk of treatment failure and death.

Special populations:

• AIDS patients: Incidence of adverse effects appears to be increased in patients with AIDS.

• Elderly: Use with caution in elderly patients; greater risk for more severe adverse reactions, including hyperkalemia associated with trimethoprim use. Elderly patients are at an increased risk for severe and potentially life-threatening hyperkalemia when trimethoprim is used concomitantly with medications known to cause or exacerbate hyperkalemia, such as spironolactone, ACE inhibitors, or ARBs (Antoniou 2010; Antoniou 2011; Antoniou, 2015).

• G6PD deficiency: Use with caution in patients with G6PD deficiency; hemolysis may occur (dose-related).

• Patients with potential for folate deficiency: Use with caution in patients with potential folate deficiency (malnourished, chronic anticonvulsant therapy, or elderly).

• Porphyria: Use with caution in patients with porphyria.

• Pregnant women: Use during pregnancy may be associated with embryo-fetal toxicity.

• Slow acetylators: May be more prone to adverse reactions.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar 2007).

• Sulfite sensitivity: Injection may contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible persons. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic persons.

Other warnings/precautions:

• Appropriate use: When used for uncomplicated urinary tract infections, this combination should not be used if a single agent is effective. Additionally, sulfonamides should not be used to treat group A beta-hemolytic streptococcal infections.

Monitoring Parameters

CBC, serum potassium, creatinine, BUN

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Sulfamethoxazole and trimethoprim cross the placenta and distribute to amniotic fluid (Ylikorkala, 1973). An increased risk of congenital malformations (neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, club foot) following maternal use of sulfamethoxazole and trimethoprim during pregnancy has been observed in some studies. Folic acid supplementation may decrease this risk (Crider 2009; Czeizel 2001; Hernandez-Diaz 2000; Hernandez-Diaz 2001; Matok 2009). Due to theoretical concerns that sulfonamides pass the placenta and may cause kernicterus in the newborn, neonatal healthcare providers should be informed if maternal sulfonamide therapy is used near the time of delivery (DHHS 2013).

The pharmacokinetics of sulfamethoxazole and trimethoprim are similar to nonpregnant values in early pregnancy (Ylikorkala 1973). Sulfamethoxazole and trimethoprim are recommended for the prophylaxis or treatment of Pneumocystis jirovecii pneumonia (PCP), prophylaxis of Toxoplasmic gondii encephalitis (TE), and for the acute and chronic treatment of Q fever in pregnancy (CDC 2013; DHHS 2013). Sulfonamides may also be used to treat other infections in pregnant women when clinically appropriate; use during the first trimester should be limited to situations where no alternative therapies are available (ACOG 2011). Because safer options are available for the treatment of urinary tract infections in pregnant women, use of TMP-containing products in the first trimester and sulfonamide-containing products >32 weeks gestation should be avoided (Lee 2008).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, or lack of appetite. Have patient report immediately to prescriber signs of a severe sulfonamide reaction (rash; red, swollen, blistered, or peeling skin; red or irritated eyes; mouth, throat, nose, or eye sores; fever, chills, or pharyngitis; cough that is new or worse; loss of strength and energy; any bruising or bleeding; or signs of liver problems like dark urine, fatigue, lack of appetite, nausea or abdominal pain, light-colored stools, vomiting, or jaundice), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, or numbness or tingling feeling), signs of aseptic meningitis (headache, fever, chills, severe nausea or vomiting, stiff neck, rash, sensitivity to lights, fatigue, or confusion), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), mood changes, hallucinations, muscle pain, joint pain, purple patches on skin or mouth, shortness of breath, severe injection site pain, burning, edema, or irritation, or signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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