Sulfamethoxazole and trimethoprim

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Sulfamethoxazole and Trimethoprim tablets and other antibacterial drugs, Sulfamethoxazole and Trimethoprim tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteriaR. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Urinary Tract Infections: For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination.

Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of pneumoniae or Haemophilus influenzae when in the judgment of the physician Sulfamethoxazole and Trimethoprim offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of Sulfamethoxazole and Trimethoprim in pediatric patients under two years of age. Sulfamethoxazole and Trimethoprim is not indicated for prophylactic or prolonged administration in otitis media at any age.

Acute Exacerbations of Chronic Bronchitis in Adults: For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician Sulfamethoxazole and Trimethoprim offers some advantage over the use of a single antimicrobial agent.

Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated.

Pneumocystis Carinii Pneumonia: For the treatment of documented Pneumocystis carinii pneumonia and for prophylaxis against Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis carinii pneumonia.

Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic E. coli.

CONTRAINDICATIONS: Sulfamethoxazole and Trimethoprim is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole and Trimethoprim is also contraindicated in pregnant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Sulfamethoxazole and Trimethoprim is contraindicated in pediatric patients less than 2 months of age. Sulfamethoxazole and Trimethoprim is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored.

WARNINGS: FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS.

SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS SULFAMETHOXAZOLE/TRIMETHOPRIM, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS).
Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

The sulfonamides should not be used for the treatment of group A - B hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Sulfamethoxazole and Trimethoprim tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficileA.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agentsA.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicatedA.

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

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

• Antibiotic, Miscellaneous
• Antibiotic, Sulfonamide Derivative

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

Acne vulgaris

Evidence from small controlled and noncontrolled trials support the use of sulfamethoxazole/trimethoprim in the treatment of moderate to severe acne vulgaris.

Based on the American Academy of Dermatology guidelines of care for the management of acne vulgaris, sulfamethoxazole and trimethoprim, in combination with topical therapy, may be considered as an alternative therapeutic option for the management of moderate and severe acne. However, use should be limited to patients who are unable to tolerate tetracycline antibiotics or in treatment resistant patients. Concomitant topical therapy with benzoyl peroxide or a retinoid should be administered with systemic antibiotic therapy (eg, sulfamethoxazole and trimethoprim) and continued for maintenance after the antibiotic course of is completed.

Bacterial meningitis

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

Bite wounds (animal)

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 clindamycin or metronidazole for anaerobic coverage, is an effective and recommended alternative for treatment of animal bite wounds.

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

IDSA guidelines cite limited data evaluating the effectiveness of trimethoprim/sulfamethoxazole 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 trimethoprim/sulfamethoxazole should be considered as alternative therapy. Trimethoprim/sulfamethoxazole can be given as a single agent or in combination with rifampin.

Diabetic foot infection

According to IDSA guidelines, sulfamethoxazole-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/trimethoprim is an effective and recommended alternative agent in the treatment of granuloma inguinale when azithromycin is not appropriate.

Head lice (Pediculosis capitis)

Most sulfamethoxazole/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/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/trimethoprim for head lice infestation if other options are available.

Isosporiasis (Isospora belli infection) 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 in the treatment of or as chronic suppressive therapy (secondary prophylaxis) of Isospora belli infection in adolescent and adult HIV-infected patients.

Melioidosis (Burkholderia pseudomallei) infection and postexposure prophylaxis

Melioidosis is a worldwide subtropic and tropic bacterial disease due to contact with Burkholderia pseudomallei contaminated water or soil [Lipsitz 2012]. A DHHS Workshop on Treatment of and Postexposure Prophylaxis for Burkholderia pseudomallei and B. mallei infection suggests the use of sulfamethoxazole and trimethoprim as initial treatment (with ceftazidime or a carbapenem) in the severe, acute phase involving brain, prostate, bone, or joint, the eradication phase and for postexposure prophylaxis of melioidosis [Lipsitz 2012]. Additional data may be necessary to further define the role of sulfamethoxazole and trimethoprim for the treatment/postexposure prophylaxis of melioidosis.

Osteomyelitis (MRSA)

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

Prosthetic joint infection

Data from a limited number of patients in a prospective, consecutive, therapeutic case series with no control group suggests that sulfamethoxazole/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.

Septic arthritis (methicillin-resistant Staphylococcus aureus)

According to IDSA guidelines, trimethoprim/sulfamethoxazole, in combination with rifampin, is a reasonable treatment option for MRSA septic arthritis.

Skin and soft tissue infections

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 skin and soft tissue infections caused by methicillin-sensitive S. aureus (MSSA) and MRSA.

Spontaneous bacterial peritonitis (prevention)

Data from controlled trials support use of trimethoprim/sulfamethoxazole 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 trimethoprim/sulfamethoxazole 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.

Surgical site infections

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 is an effective and recommended option for treatment of surgical site infections occurring after surgery of the trunk or extremity (away from the perineum or axilla). Systemic antibacterials are not routinely indicated for surgical site infections, but may be beneficial (in conjunction with suture removal plus incision and drainage) in patients with significant systemic response (eg, temperature >38.5ºC, heart rate >110 beats per minute, erythema/induration extending >5 cm from incision, WBC >12,000/mm3).

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.

Additional Off-Label Uses

Salmonella-type infections and nocardiosis; Chronic prostatitis; Treatment of Cyclospora infection and typhoid fever; Prophylaxis against urinary tract infection; Treatment of Stenotrophomonas maltophilia ventilator-associated pneumonia

Refer to adult dosing.

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

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

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.