Co-trimoxazole (Systemic) 46067 AHFS Essentials ASHPI
46067 AHFS Essentials ASHPI BATCH RIGHT Co-trimoxazole 41 A drug of choice for treatment of upper respiratory tract infections and bronchitis Co-trimoxazole (Systemic) Antibacterial; fixed combination of sulfamethoxazole (intermediate-acting sulfonamide) and trimethoprim; both sulfamethoxazole and trimethoprim are folate-antagonist antiinfectives. Class: Sulfonamides 8:12.20 (AHFS primary); AP100 (VA primary) Brands*: Bactrim; Bactrim DS; Septra; Septra DS; Sulfatrim *also available generically caused by H. influenzae; an alternative to penicillin G or penicillin V for treatment of respiratory tract infections caused by S. pneumoniae. Alternative for treatment of infections caused by Legionella micdadei† (L. pittsburgensis) or L. pneumophila†. Urinary Tract Infections (UTIs) Treatment of UTIs caused by susceptible E. coli, Klebsiella, Enterobacter, Morganella morganii, Proteus mirabilis, or P. vulgaris. A drug of choice for empiric treatment of acute uncomplicated UTIs. Brucellosis Treatment of brucellosis†; alternative when tetracyclines are contraindicated (e.g., children). Used alone or in conjunction with other anti-infectives (e.g., streptomycin or gentamicin and/or rifampin), especially for severe infections or when there are complications (e.g., endocarditis, meningitis, osteomyelitis). Synonyms: Sulfamethoxazole-Trimethoprim Abbreviations: SMX-TMP Uses Acute Otitis Media Treatment of acute otitis media (AOM) in adults† and children caused by susceptible Streptococcus pneumoniae or Haemophilus influenzae when the clinician makes the judgment that the drug offers some advantage over use of a single anti-infective. Not a drug of first choice; considered an alternative for treatment of AOM, especially for those with type I penicillin hypersensitivity. Because amoxicillin-resistant S. pneumoniae frequently are resistant to co-trimoxazole, the drug may not be effective in patients with AOM who fail to respond to amoxicillin. Data are limited regarding safety of repeated use of co-trimoxazole in pediatric patients ⬍2 years of age; the drug should not be administered prophylactically or for prolonged periods for treatment of AOM in any age group. Burkholderia Infections Treatment of infections caused by Burkholderia cepacia†. Co-trimoxazole considered drug of choice; ceftazidime, chloramphenicol, or imipenem are alternatives. Treatment of melioidosis† caused by susceptible B. pseudomallei; used in multiple-drug regimen with chloramphenicol and doxycycline. Ceftazidime or imipenem monotherapy may be preferred. B. pseudomallei is difficult to eradicate and relapse of melioidosis is common. Cholera Treatment of cholera† caused by Vibrio cholerae. Alternative to tetracyclines; used as an adjunct to fluid and electrolyte replacement in moderate to severe disease. Cyclospora Infections Treatment of infections caused by Cyclospora cayetanensis†. The drug of choice. GI Infections Granuloma Inguinale (Donovanosis) Treatment of travelers’ diarrhea caused by susceptible enterotoxigenic Escherichia Treatment of granuloma inguinale (donovanosis) caused by Calymmatobacterium top of rh base of rh cap height base of text coli. Replacement therapy with oral fluids and electrolytes may be sufficient for mild to moderate disease; those who develop diarrhea with ⱖ3 loose stools in an 8-hour period (especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in the stools) may benefit from short-term anti-infectives. Fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin, ofloxacin) usually drugs of choice when treatment indicated; co-trimoxazole also has been recommended as an alternative when fluoroquinolones cannot be used (e.g., in children). Prevention of travelers’ diarrhea† in individuals traveling forrelatively short periods to areas where enterotoxigenic E. coli and other causative bacterial pathogens (e.g., Shigella) are known to be susceptible to the drug. CDC and others do not recommend anti-infective prophylaxis in most individuals traveling to areas of risk; the principal preventive measures are prudent dietary practices. If prophylaxis is used (e.g., in immunocompromised individuals such as those with HIV infection), a fluoroquinolone (ciprofloxacin, levofloxacin, ofloxacin, norfloxacin) is preferred. Resistance to co-trimoxazole is common in many tropical areas. Treatment of enteritis caused by susceptible Shigella flexneri or S. sonnei when anti-infectives are indicated. Treatment of dysentery caused by enteroinvasive E. coli† (EIEC). AAP suggests that an oral anti-infective (e.g., co-trimoxazole, azithromycin, ciprofloxacin) can be used if the causative organism is susceptible. Treatment of diarrhea caused by enterotoxigenic E. coli† (ETEC) in travelers to resource-limited countries. Optimal therapy not established, but AAP suggests that use of co-trimoxazole, azithromycin, or ciprofloxacin be considered if diarrhea is severe or intractable and if in vitro testing indicates the causative organism is susceptible. A parenteral regimen should be used if systemic infection is suspected. Role of anti-infectives in treatment of hemorrhagic colitis caused by shiga toxinproducing E. coli† (STEC; formerly known as enterohemorrhagic E. coli) is unclear; most experts would not recommend use of anti-infectives in children with enteritis caused by E. coli 0157:H7. Treatment of GI infections caused by Yersinia enterocolitica† or Y. pseudotuberculosis†. These infections usually are self-limited, but IDSA, AAP, and others recommend anti-infectives for severe infections, when septicemia or other invasive disease occurs, and in immunocompromised patients. Other than decreasing the duration of fecal excretion of the organism, a clinical benefit of anti-infectives in management of enterocolitis, pseudoappendicitis syndrome, or mesenteric adenitis caused by Yersinia has not been established. Respiratory Tract Infections Treatment of acute exacerbation of chronic bronchitis caused by susceptible S. pneumoniae or H. influenzae when the clinician makes the judgment that the drug offers some advantage over use of a single anti-infective. granulomatis†. CDC recommends doxycycline or co-trimoxazole. Isosporiasis Treatment of isosporiasis† caused by Isospora belli. The drug of choice. Listeria Infections Treatment of infections caused by Listeria monocytogenes†; a preferred alternative to ampicillin in penicillin-allergic patients. Mycobacterial Infections Treatment of cutaneous infections caused by Mycobacterium marinum†; alternative to minocycline. Nocardia Infections Treatment of infections caused by Nocardia†, including N. asteroides, N. brasiliensis, and N. caviae. Drugs of choice are co-trimoxazole or a sulfonamide alone (e.g., sulfisoxazole, sulfamethoxazole). Pertussis Treatment of the catarrhal stage of pertussis† to potentially ameliorate the disease and reduce its communicability. Recommended by CDC, AAP, and others as an alternative to erythromycin. Prevention of pertussis† in household and other close contacts (e.g., day-care facility attendees) of patients with the disease. Alternative to erythromycin. Plague Has been used for postexposure prophylaxis of plague†. Although recommended by CDC and others for such prophylaxis in infants and children ⬍8 years of age, efficacy of the drug for prevention of plague is unknown. Most experts (e.g., CDC, AAP, the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend oral ciprofloxacin or doxycycline for postexposure prophylaxis in adults and most children. Postexposure prophylaxis recommended after high-risk exposures to plague, including close exposure to individuals with naturally occurring plague, during unprotected travel in active epizootic or epidemic areas, or laboratory exposure to viable Yersinia pestis. Has been used for treatment of plague†, but appears to be less effective than other anti-infectives used for treatment of the disease (e.g., streptomycin, gentamicin, tetracycline, doxycycline, chloramphenicol). Because of lack of efficacy, some experts state that co-trimoxazole should not be used for the treatment of pneumonic plague. short stand 46067 42 AHFS Essentials ASHPI BATCH LEFT top of rh base of rh Co-trimoxazole Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia Treatment of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP). Initial drug of choice for most patients with PCP, including HIV-infected individuals. Prevention of initial episodes of PCP (primary prophylaxis) in immunocompromised individuals at increased risk, including HIV-infected individuals. Drug of choice. up to 14 Long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence following an initial PCP episode in immunocompromised patients, including HIV-infected individuals. Drug of choice. Toxoplasmosis Prevention of toxoplasmosis† encephalitis (primary prophylaxis) in HIV-infected adults, adolescents, and children who are seropositive for Toxoplasma IgG antibody. Drug of choice. Not recommended for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence of toxoplasmosis encephalitis; regimen of choice for secondary prophylaxis of toxoplasmosis is sulfadiazine and pyrimethamine (with leucovorin). Typhoid Fever and Other Salmonella Infections Alternative for treatment of typhoid fever† (enteric fever) caused by susceptible Salmonella typhi. Drugs of choice are fluoroquinolones and third generation cephalosporins (e.g., ceftriaxone, cefotaxime); consider that multidrug-resistant strains of S. typhi (strains resistant to ampicillin, amoxicillin, chloramphenicol, and/or cotrimoxazole) reported with increasing frequency. Alternative for treatment of gastroenteritis caused by nontyphoidal Salmonella†. Wegener’s Granulomatosis Treatment of Wegener’s granulomatosis†. Effect on long-term morbidity and mortality unclear, but may prevent relapse and reduce need for cytotoxic (e.g., cyclophosphamide) and corticosteroid therapy in some patients. Whipple’s Disease Treatment of Whipple’s disease† caused by Tropheryma whippelii. Alternative or follow-up to penicillin G. Dosage and Administration Administration Administer orally or by IV infusion. Do not administer by rapid IV infusion or injection and do not administer IM. An adequate fluid intake should be maintained during co-trimoxazole therapy to prevent crystalluria and stone formation. IV Administration Dilution Co-trimoxazole concentrate for injection must be diluted prior to IV infusion. Each 5 mL of the concentrate for injection containing 80 mg of trimethoprim should be added to 125 mL of 5% dextrose in water. In patients in whom fluid intake is restricted, each 5 mL of the concentrate may be added to 75 mL of 5% dextrose in water. Rate of Administration IV solutions should be infused over a period of 60– 90 minutes. Dosage Available as fixed combination containing sulfamethoxazole and trimethoprim; dosage expressed as both the sulfamethoxazole and trimethoprim content or as the trimethoprim content. Pediatric Patients Acute Otitis Media Oral: Children ⱖ2 months of age: 8 mg/kg of trimethoprim and 40 mg/kg of sulfamethoxazole daily in 2 divided doses every 12 hours. Usual duration is 10 days. GI Infections ⬎Shigella Infections Oral: Children ⱖ2 months of age: 8 mg/kg of trimethoprim and 40 mg/kg of sulfamethoxazole daily in 2 divided doses every 12 hours. Usual duration is 5 days. IV: Children ⱖ2 months of age: 8– 10 mg/kg of trimethoprim daily (as cotrimoxazole) in 2– 4 equally divided doses given for 5 days. Urinary Tract Infections (UTIs) Oral: Children ⱖ2 months of age: 8 mg/kg of trimethoprim and 40 mg/kg of sulfamethoxazole daily in 2 divided doses every 12 hours. Usual duration is 10 days. cap height base of text ⬎Severe UTIs IV: Children ⱖ2 months of age: 8– 10 mg/kg of trimethoprim daily (as cotrimoxazole) in 2– 4 equally divided doses given for up to 14 days. Brucellosis† Oral: 10 mg/kg daily (up to 480 mg daily) of trimethoprim (as co-trimoxazole) in 2 divided doses for 4– 6 weeks. Cholera† Oral: 4– 5 mg/kg of trimethoprim (as co-trimoxazole) twice daily given for 3 days. Cyclospora Infections† Oral: 5 mg/kg of trimethoprim and 25 mg/kg of sulfamethoxazole twice daily given for 7– 10 days. HIV-infected patients may require higher dosage and longer treatment. Granuloma Inguinale (Donovanosis)† Oral: Adolescents: 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily given for ⱖ3 weeks or until all lesions have healed completely; consider adding IV aminoglycoside (e.g., gentamicin) if improvement is not evident within the first few days of therapy and in HIV-infected patients. Relapse can occur 6– 18 months after apparently effective treatment. Isosporiasis† Oral: 5 mg/kg of trimethoprim and 25 mg/kg of sulfamethoxazole twice daily. Usual duration of treatment is 10 days; higher dosage or more prolonged treatment necessary in immunocompromised patients. Pertussis† Oral: 8 mg/kg of trimethoprim and 40 mg/kg of sulfamethoxazole daily in 2 divided doses. Usual duration is 14 days for treatment or prevention. Plague† ⬎Postexposure Prophylaxis† Oral: Children ⱖ2 months of age: 320– 640 mg of trimethoprim (as cotrimoxazole) daily in 2 divided doses given for 7 days. Alternatively, 8 mg/ kg daily of trimethoprim (as co-trimoxazole) in 2 divided doses given for 7 days. Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia ⬎Treatment Oral: Children ⱖ2 months of age: 15– 20 mg/kg of trimethoprim and 75– 100 mg/kg of sulfamethoxazole daily in 3 or 4 divided doses. Usual duration is 14– 21 days. IV: Children ⱖ2 months of age: 15– 20 mg/kg of trimethoprim daily (as co-trimoxazole) in 3 or 4 equally divided doses. Usual duration is 14– 21 days. ⬎Primary Prophylaxis in Infants and Children Oral: 150 mg/m2 of trimethoprim and 750 mg/m2 of sulfamethoxazole daily in 2 divided doses given on 3 consecutive days each week. Total daily dose should not exceed 320 mg of trimethoprim and 1.6 g of sulfamethoxazole. Alternatively, 150 mg/m2 of trimethoprim and 750 mg/m2 of sulfamethoxazole can be administered as a single dose 3 times each week on consecutive days, in 2 divided doses daily 7 days each week, or in 2 divided daily doses given 3 times each week on alternate days. CDC, USPHS/IDSA, AAP, and others recommend that primary prophylaxis be initiated in all infants born to HIV-infected women starting at 4– 6 weeks of age, regardless of their CD4⫹ T-cell count. Infants who are first identified as being HIV-exposed after 6 weeks of age should receive primary prophylaxis beginning at the time of identification. Primary prophylaxis should be continued until 12 months of age in all HIVinfected infants and infants whose infection status has not yet been determined; it can be discontinued in those found not to be HIV-infected. The need for subsequent prophylaxis should be based on age-specific CD4⫹ T-cell count thresholds. In HIV-infected children 1– 5 years of age, primary prophylaxis should be initiated if CD4⫹ T-cell counts are ⬍500/ mm3 or CD4⫹ percentage is ⬍15%. In HIV-infected children 6– 12 years of age, primary prophylaxis should be initiated if CD4⫹ T-cell counts are ⬍200/mm3 or CD4⫹ percentage is ⬍15%. The safety of discontinuing prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied. short stand 46067 AHFS Essentials ASHPI BATCH RIGHT Co-trimoxazole ⬎Prevention of Recurrence (Secondary Prophylaxis) in Infants and Children Oral: 150 mg/m2 of trimethoprim and 750 mg/m2 of sulfamethoxazole daily in 2 divided doses given on 3 consecutive days each week. Total daily dose should not exceed 320 mg of trimethoprim and 1.6 g of sulfamethoxazole. 2 2 Alternatively, 150 mg/m of trimethoprim and 750 mg/m of sulfamethoxazole can be administered as a single daily dose given for 3 consecutive days each week, in 2 divided doses daily, or in 2 divided daily doses given 3 times a week on alternate days. The safety of discontinuing secondary prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied. Children who have a history of PCP should receive life-long suppressive therapy to prevent recurrence. ⬎Primary and Secondary Prophylaxis in Adolescents Oral: Dosage for primary or secondary prophylaxis against P. jiroveci pneumonia in adolescents and criteria for initiation or discontinuance of such prophylaxis in this age group are the same as those recommended for adults. (See Adult Dosage under Dosage and Administration.) Toxoplasmosis† ⬎Primary Prophylaxis in Infants and Children† Oral: 150 mg/m2 of trimethoprim and 750 mg/m2 of sulfamethoxazole daily in 2 divided doses. The safety of discontinuing toxoplasmosis prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied. Primary Prophylaxis in Adolescents† Oral: Dosage for primary prophylaxis against toxoplasmosis in adolescents and criteria for initiation or discontinuance of such prophylaxis in this age group are the same as those recommended for adults. (See Adult Dosage under Dosage and Administration.) Adults GI Infections ⬎Treatment of Travelers’ Diarrhea Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole every 12 hours given for 3– 5 days. A single 320-mg dose of trimethoprim (as cotrimoxazole) also has been used. ⬎Prevention of Travelers’ Diarrhea Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole once daily during the period of risk. Use of anti-infectives for prevention of travelers’ diarrhea generally is discouraged. ⬎Shigella Infections Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole every 12 hours given for 5 days. IV: 8– 10 mg/kg of trimethoprim daily (as co-trimoxazole) in 2– 4 equally divided doses given for 5 days. Respiratory Tract Infections ⬎Acute Exacerbations of Chronic Bronchitis Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole every 12 hours given for 14 days. Urinary Tract Infections (UTIs) Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole every 12 hours. Usual duration of treatment is 10– 14 days. A 3-day regimen may be effective for acute, uncomplicated cystitis in women. ⬎Severe UTIs IV: 8– 10 mg/kg of trimethoprim daily (as co-trimoxazole) in 2– 4 equally divided doses given for up to 14 days. Cholera† Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole every 12 hours given for 3 days. Cyclospora Infections† Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily given for 7– 10 days. HIV-infected patients may require higher dosage and longer-term treatment. Granuloma Inguinale (Donovanosis)† Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily given for ⱖ3 weeks or until all lesions have healed completely; consider adding IV aminoglycoside (e.g., gentamicin) if improvement is not evident within the first few days of therapy and in HIV-infected patients. Relapse can occur 6– 18 months after apparently effective treatment. 43 Isosporiasis† Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily. Usual duration of treatment is 10 days; higher dosage or more prolonged treatment necessary in immunocompromised patients. top of rh base of rh cap height base of text Mycobacterial Infections† ⬎Mycobacterium marinum Infections Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily given for ⱖ3 months recommended by ATS for treatment of cutaneous infections. A minimum of 4– 6 weeks of treatment usually is necessary to determine whether the infection is responding. Pertussis† Oral: 320 mg of trimethoprim (as co-trimoxazole) daily in 2 divided doses. Usual duration is 14 days for treatment or prevention. Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia ⬎Treatment Oral: 15– 20 mg/kg of trimethoprim and 75– 100 mg/kg of sulfamethoxazole daily in 3 or 4 divided doses. Usual duration is 14– 21 days. IV: 15– 20 mg/kg of trimethoprim daily in 3 or 4 equally divided doses every 6 or 8 hours given for up to 14 days. Some clinicians recommend 15 mg/kg of trimethoprim and 75 mg/kg of sulfamethoxazole daily in 3 or 4 divided doses for 14– 21 days. ⬎Primary Prophylaxis Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole once daily. Alternatively, 80 mg of trimethoprim and 400 mg of sulfamethoxazole can be given once daily. Initiate primary prophylaxis in patients with CD4⫹ T-cell counts ⬍200/mm3 or a history of oropharyngeal candidiasis. Also consider primary prophylaxis if CD4⫹ T-cell percentage is ⬍14% or there is a history of an AIDSdefining illness. Primary prophylaxis can be discontinued in adults and adolescents responding to potent antiretroviral therapy who have a sustained (ⱖ3 months) increase in CD4⫹ T-cell counts from ⬍200/mm3 to ⬎200/mm3. However, it should be restarted if CD4⫹ T-cell count decreases to ⬍200/ mm3. ⬎Prevention of Recurrence (Secondary Prophylaxis) Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole once daily. Alternatively, 80 mg of trimethoprim and 400 mg of sulfamethoxazole can be given once daily. Initiate long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) in those with a history of P. jiroveci pneumonia to prevent recurrence. Discontinuance of secondary prophylaxis is recommended in those who have a sustained (ⱖ3 months) increase in CD4⫹ T-cell counts to ⬎200/ mm3 since such prophylaxis appears to add little benefit in terms of disease prevention and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost. Reinitiate secondary prophylaxis if CD4⫹ T-cell count decreases to ⬍200/ mm3 or if P. jiroveci pneumonia recurs at a CD4⫹ T-cell ⬎200/mm3. It probably is prudent to continue secondary prophylaxis for life in those who had P. jiroveci episodes when they had CD4⫹ T-cell counts ⬎200/ mm3. Toxoplasmosis† ⬎Primary Prophylaxis Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole once daily. Alternatively, 80 mg of trimethoprim and 400 mg of sulfamethoxazole may be used. Initiate primary prophylaxis against toxoplasmosis in HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and have CD4⫹ T-cell counts ⬍100/mm3. Consideration can be given to discontinuing primary prophylaxis in adults and adolescents who have a sustained (ⱖ3 months) increase in CD4⫹ Tcell counts to ⬎200/mm3 since such prophylaxis appears to add little benefit in terms of disease prevention for toxoplasmosis, and discontinuance reduces the pill burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost. Reinitiate primary prophylaxis against toxoplasmosis if CD4⫹ T-cell count decreases to ⬍100– 200/mm3. Wegener’s Granulomatosis† Oral: 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily. short stand 46067 AHFS Essentials 44 ASHPI LEFT top of rh base of rh Co-trimoxazole Perform urinalysis with careful microscopic examination and renal function tests during co-trimoxazole therapy, especially in patients with impaired renal function. Special Populations Renal Impairment In patients with Clcr 15– 30 mL/minute, use 50% of usual dosage. Use not recommended in those with Clcr ⬍15 mL/minute. Geriatric Patients No dosage adjustments except those related to renal impairment. (See Renal Impairment under Dosage and Administration.) Cautions Contraindications • • • BATCH Known hypersensitivity to sulfonamides or trimethoprim. Documented megaloblastic anemia due to folate deficiency. Children ⬍2 months of age, pregnant women at term, and nursing women. Warnings/Precautions Warnings Severe Reactions related to the Sulfonamide Component Severe (sometimes fatal) reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, have been reported with sulfonamides. Rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice may be early indications of serious reactions. Discontinue co-trimoxazole at the first appearance of rash or any sign of adverse reactions. Superinfection/Clostridium difficile-associated Colitis Possible emergence and overgrowth of nonsusceptible bacteria or fungi. Institute appropriate therapy if superinfection occurs. Treatment with anti-infectives may permit overgrowth of clostridia. Consider Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) if diarrhea develops and manage accordingly. Some mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance alone. Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) recommended if colitis is severe. Sensitivity Reactions Hypersensitivity Reactions Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tact that have been reported with sulfonamides. Use with caution in patients with severe allergy or bronchial asthma. Sulfite Sensitivity Concentrate for injection contains a sulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals. General Precautions Patients with Folate Deficiency or G6PD Deficiency Hemolysis may occur in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency; this effect may be dose-related. Use with caution in patient with possible folate deficiency (e.g., geriatric patients, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, patients with malnutrition). Patients with Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia HIV-infected patients with Pneumocystis jiroveci pneumonia may have an increased incidence of adverse effects during co-trimoxazole therapy (particularly rash, fever, leukopenia, increased liver enzymes) compared with HIV-seronegative patients. The incidence of hyperkalemia and hyponatremia also may be increased in HIV-infected patients. Adverse effects generally are less severe in those receiving co-trimoxazole for prophylaxis rather than treatment. A history of mild intolerance to co-trimoxazole in HIV-infected patients does not appear to predict intolerance to subsequent use of the drug for secondary prophylaxis. However, use of the drug should be reevaluated in patients who develop rash or any sign of adverse reaction. Concomitant use of leucovorin and co-trimoxazole for acute treatment of P. jiroveci pneumonia in HIV-infected patients has been associated with increased rates of treatment failure and morbidity. Laboratory Monitoring Perform CBCs frequently during co-trimoxazole therapy; discontinue the drug if a significant reduction in any formed blood element occurs. cap height base of text Selection and Use of Anti-infectives To reduce development of drug-resistant bacteria and maintain effectiveness of co-trimoxazole and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria. When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. Because S. pyogenes (group A -hemolytic streptococci) may not be eradicated by co-trimoxazole, do not use the drug for treatment of infections caused by this organism since it cannot prevent sequelae such as rheumatic fever. Specific Populations Pregnancy Category C. Because sulfonamides may cause kernicterus in neonates, co-trimoxazole is contraindicated in pregnant women at term. Lactation Both sulfamethoxazole and trimethoprim distributed into milk. Co-trimoxazole contraindicated in nursing women. Pediatric Use Safety and efficacy not established in children ⬍2 months of age. Geriatric Use Geriatric patients may be at increased risk of severe adverse reactions, particularly if they have impaired hepatic and/or renal function or are receiving concomitant drug therapy. The most frequent adverse reactions in geriatric patients are severe skin reactions, generalized bone marrow suppression, or a specific decrease in platelets (with or without purpura). Those receiving concurrent therapy with a diuretic (principally thiazides) are at increased risk of thrombocytopenia with purpura. Dosage adjustments are necessary based on age-related decreases in renal function. Hepatic Impairment Use with caution in patients with impaired hepatic function. Renal Impairment Use reduced dosage in patients with Clcr 15– 30 mL/minute. Do not use in patients with Clcr ⬍15 mL/minute. Common Adverse Effects GI effects (nausea, vomiting, anorexia); dermatologic and sensitivity reactions (rash, urticaria). Interactions Specific Drugs and Laboratory Tests Drug or Test Interaction Amantadine Toxic delirium reported in an individual who received amantadine and co-trimoxazole concomitantly Antidepressants, tricyclics Possible decreased efficacy of the tricyclic antidepressant Cyclosporine Reversible nephrotoxicity reported in renal transplant recipients receiving cyclosporine and co-trimoxazole concomitantly Digoxin Possible increased digoxin concentrations, especially in geriatric patients Diuretics Possible increased incidence of thrombocytopenia and purpura if certain diuretics (principally thiazides) are used concomitantly, especially in geriatric patients Hypoglycemic agents, oral Possible potentiation of hypoglycemic effects Comments Monitor serum digoxin concentrations in patients receiving co-trimoxazole concomitantly short stand 46067 AHFS Essentials ASHPI BATCH RIGHT Co-trimoxazole Indomethacin Possible increased sulfamethoxazole concentrations Methotrexate Co-trimoxazole can displace Use caution if methotrexate methotrexate from plasma and co-trimoxazole used protein-binding sites reconcomitantly sulting in increased free methotrexate concentrations Possible interference with serum methotrexate assays if competitive protein binding technique is used with a bacterial dihydrofolate reductase as the binding protein; interference does not occur if methotrexate is measured using radioimmunoassay Co-trimoxazole may inhibit metabolism and increase half-life of phenytoin Phenytoin Monitor for possible increased phenytoin effects Tests for creatinine Possible interference with Jaffe alkaline picrate assay resulting in falsely elevated creatinine concentrations Warfarin Possible inhibition of warfarin clearance and prolonged PT mately 45– 85% of a sulfamethoxazole dose and 50– 67% of a trimethoprim dose are excreted in urine. Only small amounts of trimethoprim are excreted in feces via biliary elimination. top of rh base of rh cap height base of text Half-life Serum half-lives of sulfamethoxazole and trimethoprim are approximately 10– 13 and 8– 11 hours, respectively, in adults with normal renal function. Special Populations Patients with impaired renal function: Half-lives of both sulfamethoxazole and trimethoprim may be prolonged. In adults with Clcrⱕ10 mL/minute, serum half-life of trimethoprim may increase to ⬎26 hours. In adults with chronic renal failure, sulfamethoxazole half-life may be 3 times that in patients with normal renal function. Stability Storage Oral Tablets 15– 25C; protect from light. Megaloblastic anemia reported when co-trimoxazole used concomitantly with pyrimethamine dosages ⬎25 mg weekly (for malaria prophylaxis) Pyrimethamine 45 Suspension 15– 25C; protect from light. Parenteral Concentrate for Injection 5– 25C; do not refrigerate. Following dilution in 125 or 100 mL of 5% dextrose in water, use within 6 or 4 hours, respectively. If diluted in 75 mL of 5% dextrose in water, use within 2 hours. Compatibility Monitor PT closely and adjust warfarin dosage if cotrimoxazole used concomitantly For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Solution Compatibility Compatible Pharmacokinetics Absorption Bioavailability Sulfamethoxazole and trimethoprim are rapidly and well absorbed from the GI tract following oral administration of the fixed combination preparation (co-trimoxazole). Peak serum concentrations of both sulfamethoxazole and trimethoprim are attained within 1– 4 hours. Co-trimoxazole contains a 1:5 ratio of trimethoprim to sulfamethoxazole, but the trimethoprim:sulfamethoxazole ratio in serum after administration of the fixed-combination preparation is about 1:20 at steady-state. Dextrose 5% in sodium chloride 0.45% Ringer’s injection, lactated Variable Dextrose 5% in water Incompatible Fluconazole Linezolid Extent Acyclovir sodium Aldesleukin Allopurinol sodium Amifostine Amphotericin B cholesteryl sulfate complex Atracurium besylate Aztreonam Bivalirudin Cefepime HCl Cyclophosphamide Dexmedetomidine HCl Diltiazem HCl Docetaxel Doxorubicin HCl liposome injection Enalaprilat Esmolol HCl Etoposide phosphate Fenoldopam mesylate Filgrastim Fludarabine phosphate Gatifloxacin Gemcitabine HCl Sulfamethoxazole is approximately 70% and trimethoprim is approximately 44% bound to plasma proteins. Presence of sulfamethoxazole decreases protein binding of trimethoprim. Elimination Metabolism Both sulfamethoxazole and trimethoprim are metabolized in the liver. Elimination Route Both sulfamethoxazole and trimethoprim are rapidly excreted in urine by glomerular filtration and active tubular secretion. In adults with normal renal function, approxi- Verapamil HCl ⬎Y-Site Compatibility Compatible Plasma Protein Binding Sodium chloride 0.9% Drug Compatibility ⬎Admixture Compatibility Distribution Widely distributed into body tissues and fluids, including sputum, aqueous humor, middle ear fluid, bronchial secretions, prostatic fluid, vaginal fluid, and bile. In patients with uninflamed meninges, trimethoprim and sulfamethoxazole concentrations in CSF are about 50 and 40%, respectively, of concurrent serum concentrations. Both sulfamethoxazole and trimethoprim readily cross the placenta and are distributed into milk. Sodium chloride 0.45% Granisetron HCl Hetastarch in lactated electrolyte injection (Hextend) Hydromorphone HCl Labetalol HCl Lorazepam Magnesium sulfate Melphalan HCl Meperidine HCl Morphine sulfate Nicardipine HCl Pancuronium bromide Perphenazine Piperacillin sodium-tazobactam sodium Remifentanil HCl Sargramostim Tacrolimus Teniposide Thiotepa Vecuronium bromide Zidovudine short stand 46067 AHFS Essentials 46 ASHPI BATCH top of rh base of rh Co-trimoxazole Incompatible Tablets Fluconazole Midazolam HCl Vinorelbine tartrate Trimethoprim 80 mg and Sulfamethoxazole 400 mg* Variable Foscarnet sodium Trimethoprim 160 mg and Sulfamethoxazole 800 mg* Actions and Spectrum • • • • • • • • • LEFT A fixed combination of sulfamethoxazole and trimethoprim; both drugs are folateantagonists and sequentially inhibit enzymes of the folic acid pathway in susceptible bacteria. Sulfamethoxazole inhibits formation of dihydrofolic acid from p-aminobenzoic acid and trimethoprim inhibits formation of tetrahydrofolic acid (the metabolically active form of folic acid). Sulfamethoxazole is bacteriostatic and trimethoprim usually is bactericidal; the fixed combination generally is bactericidal when synergism is achieved. Susceptibility to trimethoprim is more critical to efficacy of co-trimoxazole than susceptibility to sulfamethoxazole. Co-trimoxazole is active against many organisms resistant to sulfamethoxazole but susceptible to trimethoprim. Spectrum of activity includes many gram-positive and -negative aerobic bacteria and some protozoa. Inactive against most anaerobic bacteria and inactive against fungi and viruses. Gram-positive aerobes: Active against Staphylococcus aureus (including penicillinase-producing strains), Streptococcus pneumoniae, S. pyogenes (group A -hemolytic streptococci), and some strains of enterococci (e.g., Enterococcus faecalis). Also active against Nocardia, but Bacilllus anthracis may be resistant. Gram-negative aerobes: Active against Acinetobacter, Enterobacter, Escherichia coli, Klbesiella pneumoniae, Morganella morganii, Proteus mirabilis, Salmonella, and Shigella. Also active against Haemophilus influenzae (including ampicillin-resistant strains), H. ducreyi, and Neisseria gonorrhoeae. Pseudomonas aeruginosa is resistant. Other organisms: Active in vitro and in vivo against Pneumocystis jiroveci (Pneumocystis carinii). Most anaerobes, including Bacteroides and Clostridium, are resistant. Resistance to co-trimoxazole has been reported in some Enterobacteriaceae and H. influenzae. Parenteral For injection concentrate, for IV infusion Trimethoprim 16 mg/mL and Sulfamethoxazole 80 mg/mL Bactrim (scored), Women First HealthCare Septra (with povidone; scored), Monarch Sulfamethoxazole and Trimethoprim Tablets, Teva, United Research Bactrim DS, Women First HealthCare Septra DS (with povidone; scored), Monarch cap height base of text Sulfamethoxazole and Trimethoprim Concentrate for Injection (with alcohol 10%, benzyl alcohol 1%, diethanolamine 0.3%, propylene glycol 40%, and sodium metabisulfite 0.1%), Sicor *available generically †Use is not currently included in the labeling approved by the US Food and Drug Administration Selected Revisions July 2005, Copyright, May 2004, American Society of Health-System Pharmacists, Inc. Advice to Patients • • • • • • Importance of completing full course of therapy, even if feeling better after a few days. Advise patients to maintain an adequate fluid intake to prevent crystalluria and stone formation. Importance of discontinuing drug and informing clinician if rash or any sign of adverse reaction (sore throat, fever, arthralgia, pallor, purpura, jaundice) occurs. Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, and any concomitant illnesses. Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed. Importance of advising patients of other important precautionary information. (See Cautions.) Preparations Co-trimoxazole Oral Suspension Trimethoprim 40 mg/5 mL and Sulfamethoxazole 200 mg/5 mL* Septra Suspension (with 0.26% alcohol, 0.1% methylparaben, and 0.1% sodium benzoate), Monarch Septra Grape Suspension (with 0.26% alcohol, 0.1% methylparaben, and 0.1% sodium benzoate), Monarch Sulfatrim Pediatric Suspension, Alpharma Sulfatrim Suspension, Alpharma, United Research short stand
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