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Sulfamethoxazole and Trimethoprim

Pronunciation

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 E. coli, Klebsiella and Enterobacter sp, M. morganii, P. mirabilis and P. vulgaris; acute otitis media; acute exacerbations of chronic bronchitis due to susceptible strains of H. influenzae or S. pneumoniae; treatment and prophylaxis of Pneumocystis pneumonia (PCP); traveler's diarrhea due to enterotoxigenic E. coli; treatment of enteritis caused by Shigella flexneri or Shigella sonnei

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

Use: Unlabeled

Cholera and Salmonella-type infections and nocardiosis; chronic prostatitis; as prophylaxis in neutropenic patients with P. jirovecii infections, in leukemia patients, and in patients following renal transplantation, to decrease incidence of PCP; treatment of Cyclospora infection, typhoid fever, melioidosis (Burkholderia pseudomallei) treatment and postexposure prophylaxis, Nocardia asteroides infection; prophylaxis against urinary tract infection; osteomyelitis due to MRSA; septic arthritis due to MRSA; skin/soft tissue infection due to community-acquired MRSA; oral phase treatment of prosthetic joint infection; chronic antimicrobial suppression of prosthetic joint infection, treatment of Q fever (Coxiella burnetii); treatment of granuloma inguinale (donovanosis); Treatment of isosporiasis (Isospora belli infection) in HIV-positive patients; treatment of Stenotrophomonas maltophilia ventilator-associated pneumonia; Toxoplasma gondii encephalitis;

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 of age (manufacturer's labeling), infants <4 weeks of age (CDC 2009); marked hepatic damage or severe renal disease (if patient not monitored)

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.

Dosing: Adult

Dosage recommendations are based on the trimethoprim component. Double-strength tablets are equivalent to sulfamethoxazole 800 mg and trimethoprim 160 mg.

General dosing guidelines:

Oral: 1 to 2 double-strength tablets (sulfamethoxazole 800 mg; trimethoprim 160 mg) every 12 to 24 hours

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

Bite wounds (animal) (off-label use) (IDSA [Stevens 2014]):

Oral: One double-strength tablet twice daily; in combination with clindamycin or metronidazole

IV: 5 to 10 mg TMP/kg/day in divided doses every 6 to 12 hours in combination with clindamycin or metronidazole

Brain abscess, empyema, and epidural abscess (MRSA) (off-label use): IV: 5 mg TMP/kg/dose every 8 to 12 hours for 4 to 6 weeks (IDSA [Liu 2011])

Chronic bronchitis (acute): Oral: One double-strength tablet every 12 hours for 10 to 14 days

Cyclosporiasis (off-label use): Oral, IV: 160 mg TMP twice daily for 7 to 10 days. Note: AIDS patients: Oral: One double-strength tablet 2 to 4 times/day for 10 days, then 1 double-strength tablet 3 times/week for 10 weeks (Pape 1994; Verdier 2000).

Diabetic foot infection (off-label use): Oral: One double-strength tablet 1 or 2 times/day. Continue therapy until resolution of infection (usually 1 to 2 weeks), but not through complete wound healing (Eleftheriadou 2010; IDSA [Lipsky 2012]; Lipsky 2004)

Granuloma inguinale (donovanosis) (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, the addition of gentamicin may be considered (CDC [Workowski 2015]).

Isosporiasis (Isospora belli infection) in HIV-infected patients (off-label use; HHS [OI adult 2015]):

Treatment: Oral, IV: 160 mg TMP 4 times/day for 10 days or 160 mg TMP 2 times/day for 7 to 10 days. May start with twice daily regimen and increase dose and/or duration up to 3 to 4 weeks if symptoms worsen or persist.

Chronic maintenance therapy (secondary prophylaxis) in patients with CD4 count <200 cells/mm3: Oral: 160 mg TMP 3 times/week (preferred) or alternatively, 160 mg TMP daily or 320 mg TMP 3 times/week.

Melioidosis (Burkholderia pseudomallei) (off-label use) (Lipsitz 2012): Oral, IV:

Severe, acute phase involving brain, prostate, bone, or joint: Administer as 2 divided doses; given with ceftazidime or a carbapenem for ≥10 days followed by eradication therapy:

Adults <40 kg: 320 mg TMP daily

Adults 40 to 60 kg: 480 mg TMP daily

Adults >60 kg: 640 mg TMP daily

Eradication therapy: Administer as 2 divided doses for ≥12 weeks:

Adults <40 kg: 320 mg TMP daily

Adults 40 to 60 kg: 480 mg TMP daily

Adults >60 kg: 640 mg TMP daily

Postexposure prophylaxis: Administer as 2 divided doses for 21 days:

Adults <40 kg: 320 mg TMP daily

Adults 40 to 60 kg: 480 mg TMP daily

Adults >60 kg: 640 mg TMP daily

Meningitis (bacterial): IV: 10 to 20 mg TMP/kg/day in divided doses every 6-12 hours

Nocardia (off-label use): Oral, IV:

Cutaneous infections: 5 to 10 mg TMP/kg/day in 2 to 4 divided doses

Severe infections (pulmonary/cerebral): 15 mg TMP/kg/day in 2 to 4 divided doses for 3 to 4 weeks, then 10 mg TMP/kg/day in 2 to 4 divided doses. Treatment duration is controversial; an average of 7 months has been reported.

Note: Therapy for severe infection may be initiated IV and converted to oral therapy (frequently converted to approximate dosages of oral solid dosage forms: 2 DS tablets every 8 to 12 hours). Although not widely available, sulfonamide levels should be considered in patients with questionable absorption, at risk for dose-related toxicity, or those with poor therapeutic response.

Osteomyelitis due to MRSA (off-label use): Oral, IV: 3.5 to 4 mg TMP/kg/dose every 8 to 12 hours for a minimum of 8 weeks with rifampin 600 mg once daily (Liu 2011)

Pneumocystis pneumonia (PCP):

Manufacturer’s labeling:

Oral:

Prophylaxis: 160 mg TMP daily

Treatment: 15 to 20 mg TMP/kg/day divided every 6 hours for 14 to 21 days

IV: Treatment: 15 to 20 mg TMP/kg/day divided every 6 to 8 hours for up to 14 days

Alternate dosing in HIV-infected patients (off-label dose; HHS [OI adult 2015]):

Primary or secondary prophylaxis: Oral: 80 or 160 mg TMP daily or alternatively, 160 mg TMP 3 times/week

Duration of prophylaxis: May discontinue primary or secondary prophylaxis if CD4 count increases from <200 cells/mm3 to ≥200 cells/mm3 for at least 3 months in response to ART; therapy must be restarted if CD4 count <200 cells/mm3

Treatment:

Mild to moderate: Oral: 15 to 20 mg TMP/kg/day in 3 divided doses for 21 days or alternatively, 320 mg TMP 3 times/day for 21 days

Moderate to severe: IV: 15 to 20 mg TMP/kg/day in 3 to 4 divided doses for 21 days; may switch to oral therapy after clinical improvement

Prosthetic joint infection (off-label use): Oral phase treatment (after completion of pathogen-specific IV therapy) following debridement and prosthesis retention or 1-stage exchange:

Total ankle, elbow, hip, or shoulder arthroplasty: 160 mg TMP 2 times daily for 3 months. Note: Must be used in combination with rifampin (Cordero-Ampuero 2007; Osmon 2013).

Total knee arthroplasty: Adults: 160 mg TMP 2 times daily for 6 months. Note: Must be used in combination with rifampin (Cordero-Ampuero 2007; Osmon 2013).

Q fever (off-label use): Oral:

Acute (in pregnant women) (CDC 2013): 160 mg TMP twice daily throughout pregnancy but not beyond 32 weeks gestation. Note: Discontinue therapy for the final 8 weeks of pregnancy due to hyperbilirubinemia risk

Chronic: Infectious Disease consult recommended for treatment of chronic Q fever

Sepsis: IV: 20 mg TMP/kg/day divided every 6 hours

Septic arthritis due to MRSA (off-label use): Oral, IV: 3.5 to 4 mg TMP/kg/dose every 8 to 12 hours for 3 to 4 weeks (some experts combine with rifampin) (Liu 2011)

Shigellosis: Note: Due to reported widespread resistance, empiric therapy with sulfamethoxazole and trimethoprim is not recommended (CDC-NARMS 2010; WHO 2005).

Oral: One double-strength tablet every 12 hours for 5 days

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

Skin/soft tissue infection due to MSSA or MRSA (off-label use): Oral: 1 to 2 double-strength tablets every 12 hours for 5 to 10 days (Lui 2011) or 7 to 14 days (IDSA [Stevens 2014]); Note: If beta-hemolytic Streptococcus spp are also suspected, a beta-lactam antibiotic should be added to the regimen (Liu 2011)

Spontaneous bacterial peritonitis (prevention) (off-label use): Oral: Long-term prophylaxis: One double-strength (trimethoprim 160 mg/sulfamethoxazole 800 mg) tablet once daily (preferred) (Lontos 2014). Daily dosing for 5 days per week has been studied (Alvarez 2005; Singh 1995), but concerns regarding bacterial resistance with intermittent dosing limit use (AASLD [Runyon 2012]). American Association for the Study of Liver Diseases (AASLD) guidelines note that intermittent dosing (ie, 5 days/week, once weekly) of antibiotics, although shown to be effective in SBP prevention, may be inferior to daily dosing due to development of bacterial resistance. Daily dosing regimens are preferred (AASLD [Runyon 2012]).

Stenotrophomonas maltophilia (ventilator-associated pneumonia) (off-label use): IV: Most clinicians have utilized 12 to 15 mg TMP/kg/day for the treatment of VAP caused by Stenotrophomonas maltophilia. Higher doses (up to 20 mg TMP/kg/day) have been mentioned for treatment of severe infection in patients with normal renal function (Looney 2009; Vartivarian 1989; Wood 2010)

Surgical site infections (trunk or extremity [away from axilla or perineum]) (off-label use): Oral: One double-strength tablet every 6 hours (IDSA [Stevens 2014])

Toxoplasma gondii encephalitis in HIV-infected patients (off-label use; HHS [OI adult 2015]: Oral:

Primary prophylaxis: Oral: 160 mg TMP daily (preferred) or 160 mg TMP 3 times/week or 80 mg TMP daily; primary prophylaxis is indicated for Toxoplasma IgG-positive patients with CD4 count <100 cells/mm3

Treatment (alternative to preferred therapy): Oral, IV: 5 mg/kg TMP twice daily for at least 6 weeks; longer duration may be needed if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.

Chronic maintenance therapy (alternative to preferred therapy): Oral: 160 mg TMP twice daily; may discontinue when asymptomatic and CD4 count >200 cells/mm3 for 6 months in response to ART

Travelers' diarrhea: Oral: One double-strength tablet every 12 hours for 5 days

Urinary tract infection:

Oral: One double-strength tablet every 12 hours

Duration of therapy: Uncomplicated: 3 to 5 days; Complicated: 7 to 10 days

Pyelonephritis: 14 days

Prostatitis: Acute: 2 weeks; Chronic: 2 to 3 months

IV: 8 to 10 mg TMP/kg/day in divided doses every 6, 8, or 12 hours for up to 14 days with severe infections

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Recommendations are based on the trimethoprim component.

General dosing guidelines: Children >2 months: Manufacturer’s labeling:

Mild-to-moderate infections: Oral: 8 mg TMP/kg/day in divided doses every 12 hours

Serious infection:

Oral: 15 to 20 mg TMP/kg/day in divided doses every 6 hours

IV: 8 to 12 mg TMP/kg/day in divided doses every 6 to 12 hours

Indication specific dosing:

Acute otitis media: Infants >2 months and Children: Oral: 8 mg TMP/kg/day in divided doses every 12 hours for 10 days. Note: Recommended by the American Academy of Pediatrics as an alternative agent in penicillin allergic patients at a dose of 6 to 10mg TMP/kg/day (AOM guidelines 2004).

Cyclosporiasis (off-label use): Infants >2 months and Children: Oral, IV: 5 mg TMP/kg twice daily for 7 to 10 days (Red Book 2009)

Head lice (Pediculosis capitis) (off-label use): Children ≥2 years: Oral: 10 mg TMP/kg/day in 2 divided doses for 7 to 10 days or 8 mg TMP/kg/day in 2 divided doses for 12 days with lindane shampoo also applied on day one (Hipolito 2001; Sim 2003).

Isosporiasis (Isospora belli infection) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Melioidosis (Burkholderia pseudomallei) (off-label use; Lipsitz 2012): Oral, IV:

Severe, acute phase involving brain, prostate, bone, or joint: Administer as 2 divided doses; given with ceftazidime or a carbapenem for ≥10 days followed by eradication therapy:

Children: 16 mg TMP/kg/day (maximum: 640 mg TMP daily)

Adolescents: Refer to adult dosing

Eradication therapy: Administer as 2 divided doses for ≥12 weeks:

Children: 16 mg TMP/kg/day (maximum: 640 mg TMP daily)

Adolescents: Refer to adult dosing

Postexposure prophylaxis: Administer as 2 divided doses for 21 days:

Children: 16 mg TMP/kg/day (maximum: 640 mg TMP daily)

Adolescents: Refer to adult dosing

Pneumocystis pneumonia (PCP):

Infants >2 months and Children:

Treatment: Manufacturer's labeling:

Oral: 15 to 20 mg TMP/kg/day in divided doses every 6 hours for 14 to 21 days

IV: 15 to 20 mg TMP/kg/day in divided doses every 6 to 8 hours for up to 14 days

Prophylaxis: Oral:

Manufacturer’s labeling: 150 mg TMP/m2/day in divided doses every 12 hours and administered for 3 days/week on consecutive (maximum: trimethoprim 320 mg and sulfamethoxazole 1,600 mg/day)

Alternate dosing: HIV-exposed/-infected patients: 150 mg TMP/m2/day in 2 divided doses daily (CDC 2009)

Adolescents: HV-infected patients (off-label dose; HHS [OI adult 2015]):

Primary prophylaxis: Oral: 80 to 160 mg TMP daily or alternatively, 160 mg TMP 3 times/week

Secondary prophylaxis: Oral: 80 to 160 mg TMP daily or alternatively, 160 mg TMP 3 times/week

Duration of prophylaxis: May discontinue primary or secondary prophylaxis if CD4 count increases from <200 cells/mm3 to ≥200 cells/mm3 for at least 3 months in response to ART; therapy must be restarted if CD4 count <200 cells/mm3

Treatment:

Mild-to-moderate: Oral: 15 to 20 mg TMP/kg/day in 3 divided doses for 21 days or alternatively, 320 mg TMP 3 times/day for 21 days

Moderate-to-severe: IV: 15 to 20 mg TMP/kg/day in 3 to 4 divided doses for 21 days; may switch to oral therapy after clinical improvement

Q fever (off-label use): Oral:

Acute: Infants ≥2 months and Children <8 years with mild or uncomplicated illness (if patient remains febrile past 5 days of doxycycline treatment): 4 to 20 mg TMP/kg/day in divided doses every 12 hours (maximum: trimethoprim 320 mg daily) (CDC 2013). Note: Some clinicians may recommend initial treatment with sulfamethoxazole and trimethoprim for children <8 years with mild or uncomplicated illness (CDC 2013; Hartzell 2008).

Chronic: Infectious Disease consult recommended for treatment of chronic Q fever (CDC 2013)

Shigellosis: 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

Alternate recommendations (off-label dose): 10 mg TMP/kg/day in divided doses every 12 hours for 5 days (Ashkenazi 1993)

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

Skin/soft tissue infection due to MSSA or MRSA (off-label use): Note: If beta-hemolytic Streptococcus spp are also suspected, a beta-lactam antibiotic should be added to the regimen (Liu 2011)

Oral: 8 to 12 mg TMP/kg/day in divided doses every 12 hours for 5 to 10 days (IDSA [Liu 2011] or 7 to 14 days (IDSA [Stevens 2014])

IV: 8 to 12 mg TMP/kg/day in divided doses every 6 hours for 7 to 14 days (IDSA [Stevens 2014])

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

Primary prophylaxis:

Infants ≥2 months 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 2013])

Adolescents: Oral: Refer to adult dosing.

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

Chronic maintenance therapy (alternative to preferred therapy): Adolescents: Oral: Refer to adult dosing.

Urinary tract infection: Infants >2 months and Children:

Treatment:

Oral: Manufacturer's labeling: 8 mg TMP/kg/day in divided doses every 12 hours for 10 days

IV: Manufacturer's labeling: 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: Oral: 2 mg TMP/kg/dose daily or 5 mg TMP/kg/dose twice weekly

Dosing: Renal Impairment

Oral, IV:

Manufacturer's labeling: Children and Adults:

CrCl >30 mL/minute: No dosage adjustment required

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

CrCl <15 mL/minute: Use is not recommended

Alternate recommendations:

CrCl 15-30 mL/minute:

Treatment: Administer full daily dose (divided every 12 hours) for 24-48 hours, then decrease daily dose by 50% and administer every 24 hours (Note: For serious infections including Pneumocystis jirovecii pneumonia (PCP), full daily dose is given in divided doses every 6-8 hours for 2 days, followed by reduction to 50% daily dose divided every 12 hours) (Nahata 1995).

PCP prophylaxis: One-half single-strength tablet (40 mg trimethoprim) daily or 1 single-strength tablet (80 mg trimethoprim) daily or 3 times weekly (Masur 2002).

CrCl <15 mL/minute:

Treatment: Administer full daily dose every 48 hours (Nahata 1995)

PCP prophylaxis: One-half single-strength tablet (40 mg trimethoprim) daily or 1 single-strength tablet (80 mg trimethoprim) 3 times weekly (Masur 2002). While the guidelines do acknowledge the alternative of giving 1 single-strength tablet daily, this may be inadvisable in the uremic/ESRD patient.

GFR <10 mL/minute/1.73 m2: Children: Use is not recommended, but if required, administer 5-10 mg trimethoprim/kg every 24 hours (Aronoff 2007).

Intermittent Hemodialysis (IHD) (administer after hemodialysis on dialysis days):

Adults: 2.5-10 mg/kg trimethoprim every 24 hours or 5-20 mg/kg trimethoprim 3 times weekly after IHD. Note: Dosing is highly dependent upon indication for use (eg, treatment of cystitis versus treatment of PCP pneumonia (Heinz 2009).

PCP prophylaxis: One single-strength tablet (80 mg trimethoprim) after each dialysis session (Masur 2002)

Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions.

Children: Use is not recommended, but if required, administer 5-10 mg trimethoprim/kg every 24 hours (Aronoff 2007).

Peritoneal dialysis (PD):

Use CrCl <15 mL/minute dosing recommendations. Not significantly removed by PD; supplemental dosing is not required (Aronoff 2007):

GFR <10 mL/minute/1.73 m2: Children: Use is not recommended, but if required 5-10 mg TMP/kg every 24 hours.

Exit-site and tunnel infections: Oral: One single-strength tablet daily (Li 2010)

Intraperitoneal: Loading dose: TMP-SMX 320/1600 mg/L; Maintenance: TMP-SMX 80/400 mg/L (Aronoff 2007; Warady 2000)

Peritonitis: Oral: One double-strength tablet twice daily (Li 2010)

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 1-2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH/CVVHD/CVVHDF: 2.5-7.5 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).

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 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.

Compatibility

Stable in D5W, D51/2NS, LR, 1/2NS; variable stability (consult detailed reference) in NS.

Y-site administration: Incompatible with caspofungin, fluconazole, midazolam, pantoprazole, vinorelbine.

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

ACE Inhibitors: Trimethoprim may enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

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: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. 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

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

Antidiabetic Agents (Thiazolidinedione): Trimethoprim may decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). 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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. 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. 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

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

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

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

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. 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. Monitor therapy

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

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

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. 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. 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. 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. 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 decrease the excretion 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. 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. 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

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

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 jiroveci pneumonia. If trimethoprim is used for another indication, monitor closely for reduced efficacy. Avoid combination

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

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 Derivatives. 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. 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. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

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

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

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. 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. 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 Derivatives 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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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 Derivatives 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): 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).

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

Perform culture and sensitivity testing prior to initiating therapy; CBC, serum potassium, creatinine, BUN

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Trimethoprim-sulfamethoxazole (TMP-SMX) crosses the placenta and distributes 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 TMP-SMX 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 TMP-SMX are similar to nonpregnant values in early pregnancy (Ylikorkala, 1973). TMP-SMX is 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; sores in your mouth, throat, nose, or eyes; fever, chills, or sore throat; cough that is new or worse; loss of strength and energy; any bruising or bleeding; or signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling), urinary retention, change in amount of urine passed, muscle pain, joint pain, purple patches on skin or mouth, shortness of breath, injection site pain or irritation, or signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose 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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