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TRIMETHOPRIM-SULFAMETHOXAZOLE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Trimethoprim and sulfamethoxazole, a combination product, is a synthetic antibacterial agent used for a wide variety of infections.

Specific Substances

    1) Abacin
    2) Apo-Sulfatrim
    3) Bactramin
    4) Bactrim
    5) Bactromin
    6) Baktar
    7) Chemotrim
    8) Co-trimoxazole
    9) Comox
    10) Cotrim-Puren
    11) Drylin
    12) Duratrimet
    13) Eltrianyl
    14) Eusaprim
    15) Fectrim
    16) Gantaprim
    17) Gantrim
    18) Helveprim
    19) Imexim
    20) Kepinol
    21) Laratrim
    22) Linaris
    23) Microtrim
    24) Momentol
    25) Nopil
    26) Omsat
    27) Septra
    28) Septrin
    29) Sigaprim
    30) Sulfotrim
    31) Sulfotrimin
    32) Sulprim
    33) Sumetrolim
    34) Supracombin
    35) Suprim
    36) TMP-SMX
    37) TMS 480
    38) Tacumil
    39) Teleprim
    40) Thiocuran
    41) Trigonyl
    42) Trimesulf
    43) Trimforte
    44) Uro-Septra
    45) Uroplus
    46) CAS 8064-90-2
    47) CAS 74711-00-5

Available Forms Sources

    A) FORMS
    1) SUSPENSION: 40 mg trimethoprim and 200 mg sulfamethoxazole per 5 mL oral suspension (Prod Info SEPTRA(R) oral tablets, 2013).
    2) TABLETS: Regular strength tablets of 400 mg of sulfamethoxazole-80 mg of trimethoprim or double strength tablets of 800 mg of sulfamethoxazole-160 mg of trimethoprim tablets (Prod Info SEPTRA(R) oral tablets, 2013).
    B) USES
    1) Trimethoprim and sulfamethoxazole is a synthetic antibacterial combination product. It is used in a wide variety of infections due to susceptible organisms, in particular those of the urinary, respiratory, and gastrointestinal tracts (e.g., urinary tract infections, acute otitis media, acute exacerbations of chronic bronchitis in adults, travelers' diarrhea in adults). It has also been used in the treatment of shigellosis, and Pneumocystis jiroveci pneumonia (Prod Info SEPTRA(R) oral tablets, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Trimethoprim and sulfamethoxazole is a synthetic antibacterial combination product. It is used in a wide variety of infections due to susceptible organisms, in particular those of the urinary, respiratory, and gastrointestinal tracts.
    B) PHARMACOLOGY: The combination of trimethoprim-sulfamethoxazole block 2 steps in the biosynthesis of nucleic acids and proteins essential to the growth of many bacteria. Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Sulfamethoxazole is able to inhibit the bacterial synthesis of dihydrofolic acid by competing with para-aminnobezoic acid (PABA).
    C) EPIDEMIOLOGY: Exposure is common, but severe toxicity is unlikely to occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Nausea and vomiting, anorexia and allergic skin reactions (e.g., rash and urticaria) are the most common adverse events. INFREQUENT: Severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias have occurred. RARE: Hypersensitivity of the respiratory tract has resulted in death in some cases.
    2) CHRONIC USE: Ongoing high dose use and/or extended periods of use may result in bone marrow depression and include thrombocytopenia, leukopenia, and/or megaloblastic anemia.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: TOXICITY: TRIMETHOPRIM: Nausea and vomiting, dizziness, headache, mental depression, confusion, and bone marrow depression can occur with a trimethoprim overdose. SULFONAMIDES: Anorexia, colic, nausea and vomiting, dizziness, headache, drowsiness, unconsciousness, pyrexia, hematuria, crystalluria, renal insufficiency, blood dyscrasias and jaundice can occur with a sulfonamide overdose.
    0.2.20) REPRODUCTIVE
    A) The trimethoprim and sulfamethoxazole combination (Bactrim(TM)) is FDA pregnancy category D. Cotrimoxazole does not appear to pose a significant teratogenic risk. Because of potential toxicity to the newborn (jaundice, hemolytic anemia, kernicterus), it is contraindicated in pregnancy near term.

Laboratory Monitoring

    A) Monitor CBC with differential, platelet count, electrolytes, serum glucose, hepatic and renal function in symptomatic patients.
    B) Monitor methemoglobin levels in cyanotic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Gastrointestinal symptoms (ie, nausea, vomiting, diarrhea) are likely to occur and mild symptoms can be managed with oral fluids; IV fluids and antiemetics may be needed if symptoms persist or become significant. Monitor urine output.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat gastrointestinal symptoms as needed. Obtain electrolytes, if symptoms persist. Monitor CNS function. Drowsiness, depression, and confusion can develop. Severe toxicity is not anticipated. RARE: In rare cases, severe bone marrow depression including thrombocytopenia, leukopenia, and/or megaloblastic anemia may develop. Severe even fatal hypersensitivity reactions have occurred with therapeutic use and may begin as a skin rash and can progress to severe reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and severe blood dyscrasias. Monitor CBC with differential and hepatic and renal function.
    C) DECONTAMINATION
    1) PREHOSPITAL: Significant toxicity is unlikely after acute ingestion and gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Administer activated charcoal in a patient with a significant ingestion or suspected coningestants that is alert and able to protect their airway or the airway is supported.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary. In the event of a hypersensitivity reaction, airway support and management may be necessary.
    E) ANTIDOTE
    1) There is no known antidote.
    F) ENHANCED ELIMINATION
    1) Techniques to enhance elimination are not likely to be necessary as severe toxicity is rare and patients usually recover with supportive care. Hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child taking an inadvertent 1 to 2 tablets can likely be monitored at home, or an asymptomatic adult taking an inadvertent extra dose can be safely managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Obtain a baseline CBC with differential, electrolytes and renal function following a significant exposure. Patients may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.
    3) ADMISSION CRITERIA: Patients experiencing severe or persistent anaphylactic symptoms or who develop evidence of blood dyscrasias should be admitted for further monitoring and treatment as indicated.
    4) CONSULT CRITERIA: Contact a medical toxicologist or regional poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    H) PREDISPOSING CONDITIONS
    1) Patients with Pneumocystis jiroveci pneumonia may develop more adverse events compared to non-AIDS patients. Symptoms may include rash, fever, leukopenia, and elevated aminotransferase values. Electrolyte abnormalities (ie, hyperkalemia and hyponatremia) have been more frequently observed in patients with P. jiroveci pneumonia treated with high dosage of trimethoprim (ie, hyperkalemia) or patients receiving trimethoprim-sulfamethoxazole therapy (ie, hyponatremia). Other patients at risk to develop hyponatremia include patients with a history of disorders of potassium metabolism, renal insufficiency and or concomitant drug therapy that may induce hyperkalemia.
    I) PHARMACOKINETICS
    1) Trimethoprim and sulfamethoxazole are rapidly absorbed. Peak plasma levels for the individual components occur 1 to 4 hours after an oral dose. Protein binding: trimethoprim, 70% and sulfamethoxazole, 44%. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. Excretion is primarily via renal excretion through both glomerular and tubular secretion.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established for trimethoprim and sulfamethoxazole. Overdoses with toxic effects have occurred following 1 gram or more of trimethoprim. Ingestion of 8 g of sulfamethoxazole and 1.6 g of trimethoprim (20 tablets) resulted in renal insufficiency in an elderly man. An iatrogenic overdose of IV trimethoprim/sulfamethoxazole (20 mg/kg/dose of trimethoprim) every 6 hours for 11 doses resulted in agitation, disorientation, psychosis and a tonic-clonic seizure.
    B) THERAPEUTIC DOSE: ADULT: Varies by indication. Range: Two regular strength tablets every 12 hours; 20 mL suspension every 12 hours or 1 double-strength tablet every 12 hours for 10 to 14 days. CHILD: OTITIS MEDIA or URINARY TRACT INFECTION: 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole every 24 hours given in divided doses every 12 hours for 10 days.

Clinical Effects

Summary Of Exposure

    A) USES: Trimethoprim and sulfamethoxazole is a synthetic antibacterial combination product. It is used in a wide variety of infections due to susceptible organisms, in particular those of the urinary, respiratory, and gastrointestinal tracts.
    B) PHARMACOLOGY: The combination of trimethoprim-sulfamethoxazole block 2 steps in the biosynthesis of nucleic acids and proteins essential to the growth of many bacteria. Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Sulfamethoxazole is able to inhibit the bacterial synthesis of dihydrofolic acid by competing with para-aminnobezoic acid (PABA).
    C) EPIDEMIOLOGY: Exposure is common, but severe toxicity is unlikely to occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Nausea and vomiting, anorexia and allergic skin reactions (e.g., rash and urticaria) are the most common adverse events. INFREQUENT: Severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias have occurred. RARE: Hypersensitivity of the respiratory tract has resulted in death in some cases.
    2) CHRONIC USE: Ongoing high dose use and/or extended periods of use may result in bone marrow depression and include thrombocytopenia, leukopenia, and/or megaloblastic anemia.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: TOXICITY: TRIMETHOPRIM: Nausea and vomiting, dizziness, headache, mental depression, confusion, and bone marrow depression can occur with a trimethoprim overdose. SULFONAMIDES: Anorexia, colic, nausea and vomiting, dizziness, headache, drowsiness, unconsciousness, pyrexia, hematuria, crystalluria, renal insufficiency, blood dyscrasias and jaundice can occur with a sulfonamide overdose.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever may occur with therapeutic use (Boyce et al, 1992).
    B) WITH POISONING/EXPOSURE
    1) Fever may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 90-year-old woman developed prolongation of the QT interval after a single dose of cotrimoxazole; on one occasion torsades de pointes resulted. After cotrimoxazole was discontinued, no additional episodes of cardiac abnormalities occurred (Lopez et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old healthy male intentionally ingested 20 tablets of propafenone (total 6000 mg) and 24 tablets of trimethoprim-sulfamethoxazole (total 1920 mg and 9600 mg, respectively) and was admitted within an hour and developed a cardiorespiratory arrest shortly after admission. He was rapidly resuscitated and transported to a higher level of care. An initial ECG showed bradycardia and a widened QRS of 260 msec with a right bundle branch block. Sinus rhythm and hemodynamic function were rapidly restored with sodium bicarbonate and dopamine. Laboratory and diagnostic (ie, transthoracic echocardiogram) studies were normal. Five hours later, a repeat ECG showed a QRS of 230 msec. On day 3, the patient was discharged with a normal ECG and no permanent sequelae. It was suggested by the authors that cardiac arrest in this case was secondary to propafenone toxicity (ie, bradycardia) and QT prolongation was associated with trimethoprim-sulfamethoxazole toxicity (Ardic et al, 2009).
    B) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 69-year-old man treated with 4 days of cotrimoxazole (1600 mg sulfamethoxazole plus 325 mg trimethoprim/day) for bronchitis developed a non-itching rash on the ears, neck, face and extremities. Two days later, the patient developed a fever which required hospitalization and was found to have necrotizing vasculitis affecting small blood vessels of the skin associated with erythema. Laboratory data evaluation demonstrated an elevated ESR, thrombocytosis, leukocytosis, and reticulocytosis. The patient's fever and skin lesions resolved spontaneously in 3 weeks with other clinical and laboratory findings resolved within 2 months (Wahlin & Rosman, 1976).
    C) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Thrombophlebitis migrans has been described during oral cotrimoxazole therapy (Verne-Pignatelli et al, 1989). Only the veins were involved, without evidence of polyarteritis nodosa or underlying malignancy. Resolution of symptoms required intravenous cyclophosphamide 200 mg on alternate days for 5 doses.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Headache may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    B) TREMOR
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An immunocompetent 29-year-old man developed an action, postural tremor one day after initiation of intravenous trimethoprim-sulfamethoxazole and oral ofloxacin for Enterobacter aerogenes meningitis. The tremor persisted and worsened to involve the tongue, trunk and extremities during the 14 days of cotrimoxazole and ofloxacin therapy. Within 2 days of drug discontinuation, the tremor resolved and the patient recovered fully. Possible mechanisms of tremor include decreased production of the dopamine precursor tyrosine and accumulation of toxic hydroxylamine metabolites in glutathione-deficient patients. It was not determined if the drug which caused the tremor was the ofloxacin or the cotrimoxazole (Patterson & Couchenour, 1999).
    2) Tremor has been temporally related to cotrimoxazole therapy in patients being treated for Pneumocystis carinii pneumonia in association with AIDS. Onset of tremors usually occurs within 3 to 6 days, with symptoms resolving 2 to 3 days after cotrimoxazole was discontinued or the dose reduced (Slavik et al, 1998; Van Gerpen, 1997; Aboulafia, 1996; Borucki et al, 1988).
    C) ANXIETY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cotrimoxazole was reported to exacerbate a panic disorder in a 48-year-old woman. The patient was being treated for a panic disorder when cotrimoxazole was initiated, and she experienced an increase in anxiety, panic attacks, and insomnia. The anxiety subsided 2 days after the cotrimoxazole was discontinued (Zealberg et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: An iatrogenic overdose of IV trimethoprim/sulfamethoxazole (20 mg/kg/dose of trimethoprim) every 6 hours for 11 doses resulted in agitation, disorientation, and psychosis over 2 days, and a tonic-clonic seizure after 7 doses in a 35-year-old. The white blood cell count and neutrophils reached a nadir of 600 and 300, respectively, 5 days after discontinuation (Personal Communication, 1988).
    D) ATAXIA
    1) WITH THERAPEUTIC USE
    a) Ataxia has been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    b) CASE SERIES: Ataxia associated with intravenous cotrimoxazole occurred in a 47-year-old man with AIDS and a 53-year-old man with non-Hodgkin's lymphoma. In the first case, the ataxia resolved 3 days after cotrimoxazole was discontinued. In the second case, the ataxia was associated with an elevated trimethoprim level of 36.4 mcg/mL. When the dose was reduced and the trimethoprim level fell, the ataxia resolved (Liu et al, 1986).
    E) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) Cotrimoxazole has been associated with delirium (McCue & Zandt, 1991).
    F) MENINGITIS
    1) WITH THERAPEUTIC USE
    a) Aseptic meningitis has been reported in several cases. Symptoms usually arise within 2 to 24 hours after initiation of therapy, and consist of headache, confusion, nausea, vomiting, stiff neck, photophobia and weakness. Seizures, abdominal pain, fever and rash have also been reported. In most cases, symptoms resolved within 48 hours of discontinuing cotrimoxazole (Prod Info SEPTRA(R) oral tablets, 2013; Andrade & Walter, 2000; Jurado et al, 1996; Blumenfeld et al, 1996; Wong et al, 1994; Davis et al, 1994; Tunkel & Starr, 1990; Birndorf & Kaufman, 1991; Joffe et al, 1989; Kremer et al, 1983; Hass, 1984).
    G) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Trimethoprim is an inhibitor of dihydropteridine reductase. Cotrimoxazole was reported to exacerbate symptoms of Parkinson's disease in a 48-month-old woman with dihydropteridine reductase deficiency. The patient had been stable while receiving therapy, including levodopa and carbidopa. Symptoms of parkinsonism and central nervous system dopamine deficiency developed after receiving 7 doses of cotrimoxazole. The symptoms resolved promptly after cotrimoxazole was discontinued (Woody & Brewster, 1990).
    H) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013; Johnson et al, 1993).
    b) CASE REPORT: A patient on high dose cotrimoxazole (duration of therapy 8 days) for presumed PCP developed 2 episodes of hypoglycemia and seizures (Johnson et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: An iatrogenic overdose of IV trimethoprim/sulfamethoxazole (20 mg/kg/dose of trimethoprim) every 6 hours for 11 doses resulted in agitation, disorientation, and psychosis over 2 days, and a tonic-clonic seizure after 7 doses in a 35-year-old. The white blood cell count and neutrophils reached a nadir of 600 and 300, respectively, 5 days after discontinuation (Personal Communication, 1988).
    I) NEURITIS
    1) WITH THERAPEUTIC USE
    a) Peripheral neuritis has been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    J) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Vertigo has been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    K) TINNITUS
    1) WITH THERAPEUTIC USE
    a) Tinnitus has been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    L) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Dizziness may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    M) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Drowsiness and unconsciousness may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    N) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Confusion may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    b) CASE REPORT: An iatrogenic overdose of IV trimethoprim/sulfamethoxazole (20 mg/kg/dose of trimethoprim) every 6 hours for 11 doses resulted in agitation, disorientation, and psychosis over 2 days, and a tonic-clonic seizure after 7 doses in a 35-year-old. The white blood cell count and neutrophils reached a nadir of 600 and 300, respectively, 5 days after discontinuation (Personal Communication, 1988).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting can developed with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea can develop shortly after the start of therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Abdominal pain may be occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Anorexia can occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    E) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) Stomatitis has been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    F) GLOSSITIS
    1) WITH THERAPEUTIC USE
    a) Glossitis has been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    G) ANTIBIOTIC ENTEROCOLITIS
    1) WITH THERAPEUTIC USE
    a) Pseudomembranous colitis has been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013; Gordin et al, 1994; Cameron & Thomas, 1977).
    b) CASE SERIES: Two HIV positive patients developed C. difficile-induced colitis after receiving cotrimoxazole for PCP prophylaxis (Gordin et al, 1994).
    H) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013; Bartels et al, 1992; Antonow, 1986).
    b) CASE REPORT: Pancreatitis, hepatitis, rhabdomyolysis and acute renal injury developed in a 22-year-old man with a recent progression to AIDS started on prophylactic double-strength trimethoprim-sulfamethoxazole therapy. Two weeks after starting therapy, he was admitted with weakness, altered mental status, nausea, and vomiting. The patient also had confirmed G6PD deficiency. He improved with drug cessation and IV fluids (Lee et al, 2012).
    c) CASE REPORT: A 50-year-old man developed acute pancreatitis after receiving cotrimoxazole for 6 weeks. The serum amylase level was 539 Units/L; the urine and serum lipase were 1550 Units/L and 905 Units/L, respectively. The symptoms resolved rapidly when cotrimoxazole was discontinued (Bartels et al, 1992).
    d) CASE REPORT: Pancreatitis occurred in a 33-year-old man following cotrimoxazole therapy for a Nocardia asteroides brain abscess. Increases in serum amylase to 461 Units/L were observed on the 16th day of cotrimoxazole therapy (normal 30 to 120 Units/L); amylase levels increased to over 1000 Units/L after approximately 20 more days of therapy. Withdrawal of cotrimoxazole resulted in resolution of symptoms within 72 hours and normalization of amylase levels within 2 weeks. Cotrimoxazole therapy was reinstituted resulting in recurrence of pancreatitis which again resolved after withdrawal (Antonow, 1986).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Hepatitis, cholestatic jaundice, hepatic necrosis, elevation of serum transaminase and bilirubin have been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    b) Cotrimoxazole rarely causes hepatotoxicity. Symptoms of hypersensitivity are commonly present in patients experiencing cotrimoxazole-induced hepatotoxicity. For this reason it is thought that an immunologic mechanism may be the cause of this reaction. In some cases, patients have been reported to recover spontaneously after cotrimoxazole is discontinued; however, the degree of liver damage may be severe, requiring aggressive treatment and deaths have been reported (Berg & Daniel, 1987).
    c) CASE REPORT: Pancreatitis, hepatitis, rhabdomyolysis and acute renal injury developed in a 22-year-old man with a recent progression to AIDS started on prophylactic double-strength trimethoprim-sulfamethoxazole therapy. Two weeks after starting therapy, he was admitted with weakness, altered mental status, nausea, and vomiting. Laboratory analysis included the following elevated levels: BUN 84 (normal, 9 to 20), aspartate 626 (normal, 17 to 59), alanine transaminase 371 (normal, 20 to 125) and total bilirubin 1.6 mg/dL (normal, 0.2 to 1.3) The patient also had confirmed G6PD deficiency. He improved with drug cessation and IV fluids (Lee et al, 2012).
    2) CASE REPORT: Acute fulminant liver failure resulting in death occurred in a 32-year-old woman who had taken a 12-day course of trimethoprim-sulfamethoxazole for a urinary tract infection. The patient presented 5 days following completion of antibiotic therapy with a full-body maculopapular pruritic rash, fever (spiking to 104 degrees F), and chills. The patient was found to have generalized lymphadenopathy, severely elevated liver enzymes, elevated direct bilirubin, eosinophilia, and atypical lymphocytes. Diagnostic imaging showed enlarged liver with ascites. She was treated with Solu-Medrol and showed improvement in liver function tests but died 3 days after hospital admission awaiting a liver transplant (Tse et al, 2000).
    3) CASE REPORT: Hepatic necrosis has been reported in an 80-year-old man treated for bilateral orchitis with cotrimoxazole 4/20 mg/kg. After a 10-day course of therapy, the drug was discontinued. However, 10 days after discontinuation of the antibiotic therapy, hepatomegaly and jaundice associated with elevated liver function tests and urine containing moderate quantities of bilirubin, urobilinogen, and protein were noted. Despite treatment, the patient's hepatomegaly and jaundice increased. The patient developed ascites and stupor. On the twenty-fifth day after discontinuation of cotrimoxazole, the patient died. Autopsy revealed massive centrilobular necrosis in a congested liver associated with cholemic necrosis, ascites and hemorrhagic diathesis. The author concluded that this fatal hepatic necrosis was caused by the trimethoprim-sulfamethoxazole combination as a result of the time course relationship between administration of the drug and onset of the jaundice (Colucci & Cicero, 1975).
    4) CASE REPORT: A 70-year-old man developed a raised rash on his legs subsequent to two different exposures to cotrimoxazole. After a third exposure consisting of 2 tablets, he developed the rash, became jaundiced and was admitted to the hospital. The patient's condition progressively declined until his death on the 32nd day after the onset of jaundice. Autopsy revealed massive hepatic necrosis. This hepatocellular type of injury is believed to be caused by acquired hypersensitivity to the sulfa drug and is not dose related (Ransohoff & Jacobs, 1981).
    5) CASE REPORT: A 16-year-old paraplegic man given cotrimoxazole (2 to 4 tablets daily) as prophylaxis against urinary tract infection developed fever, rash, eosinophilia and cholestatic hepatitis after 41 days of therapy. It was felt that the hepatic injury was of the hypersensitivity type. The few previous case reports of jaundice and allergic cholestasis with this drug combination have been associated with a history of infectious hepatitis, which was not the case with this patient (Stevenson et al, 1978).
    6) CASE REPORT: Jaundice occurred on two occasions in a 54-year-old man following cotrimoxazole administration for acute prostatitis. Approximately two months after patient's first admission for hepatitis secondary to cotrimoxazole, he was inadvertently treated again for the recurrence of prostatitis. Following three days of therapy, the patient was re-admitted with jaundice; aspiration biopsy of the liver demonstrated cholestatic hepatitis with nonspecific periportal inflammatory infiltrates compatible with drug-induced liver disease. The patient recovered in five days (Thies & Dull, 1984).
    7) CASE REPORT: A 61-year-old man receiving trimethoprim 160 mg/sulfamethoxazole 800 mg twice a day for a chronic bladder infection developed pruritus followed by jaundice within 1 month. Laboratory revealed a total bilirubin of 8.8 mg/dL, alkaline phosphatase of 225 Milliunits/mL, and SGOT of 60 Milliunits/mL. Upon hospitalization liver biopsy revealed centrilobular cholestasis with bile casts and some hepatocyte degeneration. Ten days following discontinuation of cotrimoxazole, symptoms began to resolve and liver-function tests returned to normal ranges (Nair et al, 1980).
    8) CASE REPORT: Intrahepatic cholestasis was described in a 65-year-old man following cotrimoxazole therapy (Septrin(R), 2 tablets BID) for approximately 4 weeks (Oliver et al, 1987). Hepatic biopsy demonstrated cholestasis, around and in the centrilobular hepatocytes, with bile plugging. Withdrawal of the drug resulted in slow clinical improvement over the next several months; jaundice persisted for 4 weeks after drug withdrawal.
    9) CASE REPORT: A 22-year-old woman developed a rash and progressive jaundice after 2 weeks of treatment with trimethoprim 160 mg and sulfamethoxazole 800 mg daily (Cario et al, 1996). SGPT and SGOT levels increased to 328 Units/L and 83 Units/L, respectively, and total bilirubin increased to 5.9 mg/dL. A liver biopsy revealed central acinar cholestasis. A lymphocyte transformation test confirmed that the reaction was allergic in nature. The patient recovered after 8 weeks without specific treatment.
    B) JAUNDICE
    1) WITH POISONING/EXPOSURE
    a) Jaundice may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria have been reported with therapy (Prod Info SEPTRA(R) oral tablets, 2013; Ainapurapu & Kanakadandi, 2014).
    b) Sulfamethoxazole and trimethoprim have been implicated as nephrotoxic, especially in patients with pre-existing renal impairment. However, some data suggest that this is not conclusive and their combined use is safe and effective in renal patients (Rosenfeld et al, 1975; Bennett & Craven, 1976).
    c) CASE SERIES: Renal function declined in 16 patients in association with cotrimoxazole treatment. This was reversible in most, but 3 patients showed permanent impairment of renal function. In 5 patients with impaired renal function in whom a modification of the standard dose regimen was used, renal function further deteriorated. The authors suggest that cotrimoxazole should not be used when the serum creatinine is above 2 mg per 100 mL (Kalowski et al, 1973).
    d) CASE REPORT: Pancreatitis (lipase 1326 Units/L (normal, 23 to 300), hepatitis, rhabdomyolysis and acute renal injury developed in a 22-year-old man with a recent progression to AIDS started on prophylactic double-strength trimethoprim-sulfamethoxazole therapy. Two weeks after therapy began, he was admitted with weakness, altered mental status, nausea, and vomiting. The patient also had confirmed G6PD deficiency. He improved with drug cessation and IV fluids (Lee et al, 2012).
    e) CASE REPORT: Acute granulomatous interstitial nephritis due to cotrimoxazole has been described in a 51-year-old man (Cryst & Hammar, 1988). Five days after starting oral cotrimoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole twice daily), the patient developed a generalized pruritic maculopapular rash, fever, and dark urine. Serum creatinine was elevated to 3.7 mg/dL. Percutaneous renal biopsy revealed interstitial granulomas.
    f) CASE SERIES: Two patients developed crystalluria when given intravenous cotrimoxazole, who were also septicemic and hypoproteinemic (Buchanan, 1978).
    g) CASE REPORT: A 72-year-old man being treated for chronic prostatitis for 2 weeks with cotrimoxazole (no dose given) developed oliguria and dramatic increases of BUN and serum creatinine (Siegal, 1977). After surgical removal of bilateral ureteral obstructions, profound diuresis began. One obstruction was composed of pure cotrimoxazole metabolites.
    2) WITH POISONING/EXPOSURE
    a) Crystalluria may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).
    b) CASE REPORT: Renal insufficiency and obstruction of the Foley catheter was reported in a 70-year-old man with urinary retention who ingested 20 cotrimoxazole tablets (8 grams of sulfamethoxazole and 1.6 grams of trimethoprim). Renal function improved by the fourth day (Goff, 1989).
    B) CRUSH SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Acute tubular necrosis (confirmed by biopsy), bone marrow and liver involvement, and scrotal skin infarction were seen in a 78-year-old man within 48 hours of beginning a regimen of co-trimoxazole (dose not given) and floxacillin (500 mg every 8 hours) (Rudra et al, 1989).
    C) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Hematuria may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Compensated metabolic acidosis has occurred in 6 HIV-infected patients receiving high-dose cotrimoxazole. Onset of symptoms has generally occurred within 3 to 5 days of therapy (20 mg/kg trimethoprim component intravenously), with symptoms resolving 2 to 3 days after discontinuation of therapy or bicarbonate administration (Porras et al, 1998).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, pancytopenia, and eosinophilia have been reported with therapeutic use (Prod Info SEPTRA(R) oral tablets, 2013; Tapp & Savarirayan, 1997).
    b) CASE SERIES: Neutropenia developed in 34% and thrombocytopenia in 12% of 50 children treated with trimethoprim/sulfamethoxazole for 10 days for otitis media or uncomplicated UTI (Asmar et al, 1981).
    c) It has reportedly been associated with thrombocytopenia. Thrombocytopenia is often associated with megaloblastic anemia and therefore, the simultaneous administration of cotrimoxazole can lead to even more severe thrombocytopenia. Cotrimoxazole appears to increase the severity of megaloblastic changes which in turn lead to reduction in platelets (Anon, 1973a; Rickard & Uhr, 1971; McPherson, 1970; Hammett, 1970; Mohan, 1969).
    d) CASE SERIES: Two patients developed thrombocytopenic purpura and vaginal bleeding while receiving cotrimoxazole. The platelet count was 2,000/microliter in both patients. One patient responded to corticosteroids, and the other responded to a combination of corticosteroids and intravenous immunoglobulin (Herrington et al, 1994).
    e) HEMOLYTIC ANEMIA: Cotrimoxazole has been associated with hemolytic anemia in a few case studies; most patients were deficient in glucose-6-phosphate dehydrogenase (G6PD) (Taraszewski et al, 1989; Chan & McFadzean, 1974; Owusu, 1972). Hemolytic anemia has been associated with the sulfamethoxazole component (Chan & McFadzean, 1974) (Chan et el, 1976).
    f) METHEMOGLOBINEMIA (methemoglobin level of 18.3%) associated with cyanosis of 24 hours' duration was reported in a 22-year-old woman 8 days after receiving sulfamethoxazole and trimethoprim therapy for urinary tract infection (Damergis et al, 1983).
    2) WITH POISONING/EXPOSURE
    a) Blood dyscrasia may occur with overdose (Prod Info SEPTRA(R) oral tablets, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Drug eruptions included erythema multiforme, allergic or toxic dermatitis, maculopapular rash, exfoliative eczema exanthema, and Stevens-Johnson syndrome (Tse et al, 2000; Cario et al, 1996; Cryst & Hammar, 1988; Cohn et al, 1984; Gutman, 1984; Personal Communication, 1982; Ransohoff & Jacobs, 1981; Nair et al, 1980; Stevenson et al, 1978).
    b) Cutaneous reactions to cotrimoxazole prophylactically or therapeutically for P. carinii pneumonia in patients with AIDS (with or without Kaposi's sarcoma) has been reported up to 69% of the time. The rash generally occurred 4 days after initiation of therapy (1 to 9 days) and consisted of maculopapular cutaneous eruptions (Mitsuyasu & Groopman, 1983).
    c) RISK FACTOR: An increased incidence of Stevens Johnson Syndrome among HIV-infected patients occurs due to the hydroxylamine derivative of sulfamethoxazole, which results in a deficiency of glutathione enzyme resulting in a decreased capacity to scavenge hydroxylamine derivatives (Taqi et al, 2012).
    d) CASE REPORT: A 33-year-old man with Pneumocystis jiroveci developed fever and severe painful erythematous, maculopapular and vesicular lesions consistent with Stevens Johnson syndrome about 12 days after starting trimethoprim-sulfamethoxazole therapy. Therapy was stopped and he was treated aggressively with IV dexamethasone, fluids and prophylactic antibiotics. He gradually recovered (Taqi et al, 2012).
    e) SWEET'S SYNDROME, also known as ACUTE FEBRILE NEUTROPHILIC DERMATOSIS, is characterized by peripheral neutrophilia, high sedimentation rate, fever, joint and muscle pains, painful plaques and pseudoblisters, and conjunctivitis. Sweet's syndrome occurred 2 days after initiating cotrimoxazole therapy for the treatment of diarrhea. Papulovesicles and plaques developed on sun exposed areas of the skin. Symptoms resolved rapidly upon discontinuation of cotrimoxazole and topical administration of fluocinonide cream (Walker & Cohen, 1996).
    f) CASE REPORT: Generalized erythema of the skin and purple-black discoloration of the scrotum were seen in a 78-year-old man within 48 hours of starting a regimen of co-trimoxazole (no dose given) and floxacillin (500 mg every 8 hours) (Rudra et al, 1989).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens Johnson Syndrome is a rare adverse event of therapy but in rare cases it has been associated with fatalities (Prod Info SEPTRA(R) oral tablets, 2013).
    C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis (TEN) has been reported in isolated case reports in association with cotrimoxazole. In these cases, TEN occurred 9 to 17 days after initiation of therapy and was often preceded by a generalized rash, fever, chills, and muscle aches. Two of these cases have occurred in patients seropositive for HIV. Skin sloughing may continue after cotrimoxazole is discontinued (Senneville et al, 1991; Romeu et al, 1989; Whittington, 1989).
    D) GENERALIZED EXFOLIATIVE DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Exfoliative dermatitis occurred in a 6-year-old girl after taking cotrimoxazole for less than 10 days. Three days after cotrimoxazole was discontinued, a generalized rash appeared, which then faded from the trunk becoming confined to the extremities. Desquamation occurred on the feet and not on any other part of the body (Ponte et al, 1990).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia has been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia has been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013).
    C) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Pancreatitis, hepatitis, rhabdomyolysis and acute renal injury developed in a 22-year-old man with a recent progression to AIDS started on prophylactic double-strength trimethoprim-sulfamethoxazole therapy. two weeks after starting therapy, he was admitted with weakness, altered mental status, nausea, and vomiting . Upon admission, CPK was 20057 and declined to 8350 on the day of discharge. The patient also had confirmed G6PD deficiency. He improved with drug cessation and IV fluids (Lee et al, 2012).
    b) CASE REPORT: Rhabdomyolysis developed in a 40-year-old healthy woman after taking 4 doses of trimethoprim-sulfamethoxazole (TMP-SMX) empirically for a presumed urinary tract infection. Two days prior to admission, she developed muscle aches and lower extremity weakness. Serum creatinine phosphokinase was 20,063 International Units/L (normal, 15 to 28) on admission along with an elevated creatinine of 1.5 mg/dL (normal, 0.6 to 1.1). Following discontinuation of TMP-SMX and IV fluid therapy, muscle tenderness, weakness and acute kidney injury improved. Creatinine phosphokinase decreased to 760 International Units/L (Ainapurapu & Kanakadandi, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoglycemia has been reported with therapeutic use of sulfamethoxazole and fixed-dose combinations of trimethoprim/sulfamethoxazole (Prod Info SEPTRA(R) oral tablets, 2013; Lee & Maddix, 1997; Frankel et al, 1984; Arem et al, 1983; Craft et al, 1977).
    b) In most cases, patients have pre-existing renal impairment or end stage renal failure, with no dosing adjustments to reflect this renal impairment. Hypoglycemia (as low as 26 mg/dL) has occurred within 1.5 hours to 5 days of therapy. Following a dose reduction of cotrimoxazole according to renal function and concomitant dextrose supplements, hypoglycemia generally has resolved with no further sequelae (Lee & Maddix, 1997; Johnson et al, 1993; Frankel et al, 1984).
    c) Because sulfonamides are chemically similar to sulfonylureas, the mechanism of this adverse effect is thought to be the same as that for oral hypoglycemic agents. It is thought that the sulfamethoxazole portion of cotrimoxazole binds to receptors on the pancreatic islet cells causing the release of insulin. Patients with a creatinine clearance less than 30 milliliters/minute should receive adjusted doses of cotrimoxazole (Prod Info Septra(R), trimethoprim and sulfamethoxazole, 2000; Lee & Maddix, 1997; Johnson et al, 1993; Frankel et al, 1984).
    1) In one patient, elevated C-peptide serum levels was consistent with the theory that cotrimoxazole stimulates islet cells causing the release of excess insulin (Johnson et al, 1993).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) CELL-MEDIATED IMMUNE REACTION
    1) WITH THERAPEUTIC USE
    a) The following allergic reactions have been reported following therapy: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schonlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, rash, periarteritis nodosa, systemic lupus erythematosus (Prod Info Septra(R), trimethoprim and sulfamethoxazole, 2000; Platt et al, 1988).
    b) The sulfamethoxazole component of cotrimoxazole is often implicated in hypersensitivity reactions; however, the trimethoprim component should also be considered (Cabanas et al, 1996).
    c) In patients without AIDS, adverse reactions to cotrimoxazole are reported in 8% of patients and hypersensitivity type reactions in 3.3%. In patients with AIDS, hypersensitivity reactions to cotrimoxazole, although usually mild, occur commonly. Mild skin rashes occur in 24% to 50% of AIDS patients and severe skin rashes involving mucous membranes have been reported in 0% to 20% of patients. In general, if the hypersensitivity reaction is considered mild, the patient may be rechallenged or desensitized with cotrimoxazole and are able to tolerate further therapy (Palusci et al, 1996; Jung & Paauw, 1994; Kletzel et al, 1991; Kreuz et al, 1990).

Reproductive

    3.20.1) SUMMARY
    A) The trimethoprim and sulfamethoxazole combination (Bactrim(TM)) is FDA pregnancy category D. Cotrimoxazole does not appear to pose a significant teratogenic risk. Because of potential toxicity to the newborn (jaundice, hemolytic anemia, kernicterus), it is contraindicated in pregnancy near term.
    3.20.2) TERATOGENICITY
    A) SULFAMETHOXAZOLE AND TRIMETHOPRIM
    1) In a retrospective study of 186 pregnancies, the incidence of congenital abnormalities was 3.3% (4 of 120) in infants born to mothers who received sulfamethoxazole and trimethoprim during pregnancy as compared with 4.5% (3 of 66) for those who received placebo. In the 10 infants whose mothers received the drug combination during the first trimester in this study, no abnormalities were reported (Brumfitt & Pursell, 1973). In a separate survey in which 35 infants whose mothers received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter, the authors also reported no congenital abnormalities (Prod Info BACTRIM(TM) oral tablets oral double strength tablets, 2013; Prod Info sulfamethoxazole and trimethoprim IV injection, 2009).
    2) In some retrospective epidemiologic studies, an association between first trimester exposure to sulfamethoxazole and trimethoprim combination with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot, was suggested. However, these studies were limited by the small number of exposed patients, the lack of adjustment for multiple statistical comparison and confounders, recall, selection, and information biases, and generalizability of their findings. In other epidemiological studies, no statistically significant association between sulfamethoxazole and trimethoprim exposure and specific malformation was observed (Prod Info BACTRIM(TM) oral tablets oral double strength tablets, 2013).
    B) COTRIMOXAZOLE
    1) Cotrimoxazole does not appear to pose a significant teratogenic risk, however. Because of potential toxicity to the newborn (jaundice, hemolytic anemia, kernicterus), it is contraindicated in pregnancy near term. Sulfonamides compete with bilirubin for binding to plasma albumin, and result in kernicterus in the newborn infant. Other toxicities which have been reported in the newborn following maternal exposure include jaundice and hemolytic anemia. Trimethoprim crosses the placenta, but there are no case reports demonstrating an increase in fetal abnormalities (Briggs et al, 1998; Bailey, 1984; Azad Khan & Truelove, 1979; Hensleigh & Kauffman, 1977).
    C) ANIMAL STUDIES
    1) RATS
    a) Oral doses of 533 mg/kg sulfamethoxazole or 200 mg/kg of trimethoprim in rats resulted in teratologic effects, mainly cleft palates. The highest dose of separately administered agents that did not cause cleft palates in rats was 512 mg/kg of sulfamethoxazole and 192 mg/kg of trimethoprim. While no teratology was observed when 512 mg/kg of sulfamethoxazole and 128 mg/kg of trimethoprim were administered in combination to rats in 2 studies, cleft palates were noted in 1 litter out of 9 when 355 mg/kg of sulfamethoxazole and 88 mg/kg of trimethoprim were used in combination in another study of rats (Prod Info BACTRIM(TM) double strength oral tablets, oral tablets, 2012; Prod Info sulfamethoxazole and trimethoprim IV injection, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) U.S. Food and Drug Administration's Pregnancy Category D (Prod Info BACTRIM(TM) oral tablets oral double strength tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) The trimethoprim and sulfamethoxazole combination is excreted in breast milk at levels approximately 2% to 5% of the recommended daily dose for infants over 2 years of age. Due to the potential risk of bilirubin displacement and kernicterus, caution is recommended when administering trimethoprim and sulfamethoxazole to a nursing woman, especially if breastfeeding an infant who is jaundiced, ill, stressed, or premature (Prod Info BACTRIM(TM) oral tablets oral double strength tablets, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Rats administered oral sulfamethoxazole 350 mg/kg/day plus trimethoprim 70 mg/kg/day (approximately 2 times the recommended human daily dose on a body surface area basis) had no observed adverse effects on fertility or general reproductive performance (Prod Info BACTRIM(TM) oral tablets oral double strength tablets, 2013).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) In a 26-week tumorigenic mouse (Tg-rasH2) study, sulfamethoxazole was not carcinogenic at doses up to 400 mg/kg/day (2.4 times the human systemic exposure at a dose of 800 mg twice daily) (Prod Info BACTRIM(TM) oral tablets oral double strength tablets, 2013).

Genotoxicity

    A) There was no evidence of genotoxicity or mutagenicity from the following tests of the sulfamethoxazole and trimethoprim combination: in vitro chromosomal aberration assay in human lymphocytes, in vitro and in vivo tests in animal species, and observations for chromosomal abnormalities in leukocytes obtained from patients. The sulfamethoxazole and trimethoprim combination was not assessed for mutagenicity using the in vitro reverse mutation bacterial tests according to standard protocol. Sulfamethoxazole monotherapy was positive in the following tests using cultured human lymphocytes: in vitro reverse mutation bacterial and in vitro micronucleus assays. Trimethoprim monotherapy was positive in the following tests using cultured human lymphocytes: in vitro Comet, micronucleus, and chromosomal damage assays. Trimethoprim monotherapy was negative in the following tests using Chinese hamster ovary or lung cells with or without S9 activation: in vitro reverse mutation bacterial and chromosomal aberration assays. No evidence of DNA damage was observed in mice administered oral trimethoprim using Comet assays of liver, kidney, lung, spleen, or bone marrow (Prod Info BACTRIM(TM) oral tablets oral double strength tablets, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Cough, shortness of breath, and pulmonary infiltrates have been reported following therapy (Prod Info SEPTRA(R) oral tablets, 2013; Cass, 1987).
    b) CASE REPORT: An 81-year-old woman developed chills, cough and dyspnea within 5 to 6 hours after the ingestion of a single cotrimoxazole tablet (160 mg trimethoprim/800 mg sulfamethoxazole) on 3 separate occasions. Chest radiographs on each occasion demonstrated diffuse interstitial infiltrates. The patient had been taking the drug for recurrent sinusitis. Following the third incident, a right lower lobe lobectomy was performed to remove a well circumscribed squamous cell carcinoma. The patient had no further episodes and did not receive further cotrimoxazole therapy (Cass, 1987).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC with differential, platelet count, electrolytes, serum glucose, hepatic and renal function in symptomatic patients.
    B) Monitor methemoglobin levels in cyanotic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients experiencing severe or persistent anaphylactic symptoms or who develop evidence of blood dyscrasias should be admitted for further monitoring and treatment as indicated.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child taking an inadvertent 1 to 2 tablets can likely be monitored at home, or an asymptomatic adult taking an inadvertent extra dose can be safely managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or regional poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Obtain a baseline CBC with differential, electrolytes and renal function following a significant exposure. Patients may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.

Monitoring

    A) Monitor CBC with differential, platelet count, electrolytes, serum glucose, hepatic and renal function in symptomatic patients.
    B) Monitor methemoglobin levels in cyanotic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Significant toxicity is unlikely after acute ingestion and gastrointestinal decontamination is generally unnecessary. Decontamination should be considered in patients with significant coingestants or extremely large ingestions.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Significant toxicity is unlikely after an acute ingestion and gastrointestinal decontamination is generally unnecessary. Decontamination should be considered in patients with significant coingestants or extremely large ingestions.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Obtain a baseline CBC, electrolytes (blood sugar), hepatic and renal function test.
    C) ACUTE ALLERGIC REACTION
    1) The drug should be immediately discontinued, if the patient develops any evidence of hypersensitivity reactions or anaphylactic shock.
    D) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) FLUID IMBALANCE
    1) Administer oral or intravenous fluids to maintain adequate urine output in patients that develop significant vomiting and/or diarrhea.
    G) SEIZURE
    1) Seizure activity has been reported infrequently with therapy (Prod Info SEPTRA(R) oral tablets, 2013) and has been reported in overdose in a limited number of patients.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    H) MYELOSUPPRESSION
    1) Blood dyscrasias, such as leukopenia or neutropenia, megaloblastic anemia, and thrombocytopenia may occur following use. Administer leucovorin (folinic acid) in doses of 5 to 15 mg daily if bone marrow depression occurs, and repeat as necessary (Prod Info SEPTRA(R) oral tablets, 2013).
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    3) THROMBOCYTOPENIA: Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.

Enhanced Elimination

    A) SUMMARY
    1) Techniques to enhance elimination are not likely to be necessary as severe toxicity is rare and patients do well with supportive care.
    B) HEMODIALYSIS
    1) Hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole (Prod Info SEPTRA(R) oral tablets, 2013).
    C) PERITONEAL DIALYSIS
    1) Peritoneal dialysis is NOT effective (Prod Info SEPTRA(R) oral tablets, 2013).
    D) URINARY ACIDIFICATION/NOT RECOMMENDED
    1) ACIDIFICATION OF THE URINE will increase renal elimination of trimethoprim (Prod Info SEPTRA(R) oral tablets, 2013), but is not recommended.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established for trimethoprim and sulfamethoxazole. Overdoses with toxic effects have occurred following 1 gram or more of trimethoprim. Ingestion of 8 g of sulfamethoxazole and 1.6 g of trimethoprim (20 tablets) resulted in renal insufficiency in an elderly man. An iatrogenic overdose of IV trimethoprim/sulfamethoxazole (20 mg/kg/dose of trimethoprim) every 6 hours for 11 doses resulted in agitation, disorientation, psychosis and a tonic-clonic seizure.
    B) THERAPEUTIC DOSE: ADULT: Varies by indication. Range: Two regular strength tablets every 12 hours; 20 mL suspension every 12 hours or 1 double-strength tablet every 12 hours for 10 to 14 days. CHILD: OTITIS MEDIA or URINARY TRACT INFECTION: 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole every 24 hours given in divided doses every 12 hours for 10 days.

Therapeutic Dose

    7.2.1) ADULT
    A) DOSE FORMS
    1) A single strength (SS) tablet contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole. A double strength (DS) tablet is 160 mg of trimethoprim and 800 mg of sulfamethoxazole (Prod Info BACTRIM(TM) double strength oral tablets, oral tablets, 2012). A 5-mL vial of the IV form contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim (Prod Info sulfamethoxazole and trimethoprim IV injection, 2009). Each 5 mL of the oral suspension contains 200 mg of sulfamethoxazole and 40 mg of trimethoprim (Prod Info sulfamethoxazole and trimethoprim oral suspension, 2010).
    B) TREATMENT
    1) PNEUMOCYSTIS JIROVECI PNEUMONIA
    a) ORAL TABLET OR SUSPENSION: 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim orally per day (divided every 6 hours) for 14 to 21 days (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013).
    b) IV: 15 to 20 mg/kg/day trimethoprim component divided into 3 to 4 equal doses every 6 to 8 hours for up to 14 days (Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    2) SHIGELLOSIS OR TRAVELLER'S DIARRHEA
    a) ORAL TABLETS OR SUSPENSION: 1 double-strength tablet or 2 single-strength tablets or 20 mL suspension orally every 12 hours for 5 days (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013).
    b) IV: 8 to 10 mg/kg trimethoprim component/day IV in 2 to 4 equally divided doses every 6, 8, or 12 hours for 5 days. MAXIMUM DOSE: 60 mL/day (Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    3) URINARY TRACT INFECTION OR ACUTE EXACERBATION OF CHRONIC BRONCHITIS
    a) ORAL: 1 double-strength tablet or 2 single-strength tablets or 20 mL suspension orally every 12 hours for 10 to 14 days (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013).
    b) IV: 8 to 10 mg/kg trimethoprim component/day IV in 2 to 4 equally divided doses every 6, 8, or 12 hours for up to 14 days. MAXIMUM DOSE: 60 mL/day (Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    C) PROPHYLAXIS
    1) ORAL: 1 double-strength tablet daily OR 20 mL suspension daily (Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole and trimethoprim oral suspension, 2010).
    7.2.2) PEDIATRIC
    A) DOSE FORMS
    1) A single strength (SS) tablet contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole. A double strength (DS) tablet is 160 mg of trimethoprim and 800 mg of sulfamethoxazole (Prod Info BACTRIM(TM) double strength oral tablets, oral tablets, 2012). A 5-mL vial of the IV form contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim (Prod Info sulfamethoxazole and trimethoprim IV injection, 2009). Each 5 mL of the oral suspension contains 200 mg of sulfamethoxazole and 40 mg of trimethoprim (Prod Info sulfamethoxazole and trimethoprim oral suspension, 2010).
    B) TREATMENT
    1) PNEUMOCYSTIS JIROVECI PNEUMONIA
    a) PROPHYLAXIS
    1) INFANTS LESS THAN 2 MONTHS OF AGE: Contraindicated (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013; Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    2) IV: 15 to 20 mg/kg/day trimethoprim component divided into 3 to 4 equal doses every 6 to 8 hours for up to 14 days (Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    3) 2 MONTHS TO 12 YEARS: The recommended dose is 750 mg/m(2)/day sulfamethoxazole and 150 mg/m(2)/day trimethoprim in 2 divided doses orally 3 times a week on consecutive days (MAX 1600 mg/day sulfamethoxazole and 320 mg/day trimethoprim) (Prod Info SEPTRA(R) oral tablets, 2013). Alternate dosing schedules for the same dosage include: single dose orally 3 times weekly on consecutive days, 2 divided doses orally daily, or 2 divided doses orally 3 times weekly on alternate days (Centers for Disease Control and Prevention et al, 2009; Tomblyn et al, 2009). It is recommended that infants born to HIV-infected women be considered for prophylaxis beginning at 4 to 6 weeks of age (Centers for Disease Control and Prevention et al, 2009).
    4) 13 YEARS AND OLDER: 1 double strength tablet (trimethoprim 160 mg/sulfamethoxazole 800 mg) orally once daily or 1 single strength tablet (trimethoprim 80 mg/sulfamethoxazole 400 mg) orally once daily. May also administer 1 double strength tablet (trimethoprim 160 mg/sulfamethoxazole 800 mg) orally three times weekly (Centers for Disease Control and Prevention et al, 2009a; Tomblyn et al, 2009).
    5) A twice weekly (8 mg/kg/day (based on trimethoprim component) divided twice daily on 2 nonconsecutive days) prophylaxis regimen was reported effective in a retrospective study of pediatric patients undergoing chemotherapy (n=86) or HCT (n=61). No breakthrough cases of PCP were reported (Ohata et al, 2009). A twice weekly (150 mg/m(2)/day or 5 mg/kg/day (based on trimethoprim component) divided twice daily on 2 consecutive days) prophylaxis regimen was also reported effective in 2 retrospective studies (n=87 and n=482) of pediatric patients with leukemia or lymphoma. No breakthrough cases of PCP were reported in compliant patients in either study (Agrawal et al, 2011; Lindemulder & Albano, 2007).
    b) TREATMENT
    1) INFANTS LESS THAN 2 MONTHS OF AGE: Contraindicated (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013; Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    2) 2 MONTHS TO 12 YEARS: 5 to 20 mg/kg/day (based on trimethoprim component) orally in divided doses every 6 to 8 hours for 21 days (Prod Info sulfamethoxazole and trimethoprim oral suspension, 2010; Prod Info BACTRIM(TM) double strength tablets, oral tablets, 2010; Centers for Disease Control and Prevention et al, 2009). For HIV-infected children, IV therapy is recommended first (15 to 20 mg/kg/day in divided doses every 6 to 8 hours) followed by oral therapy after clinical improvement to complete a 21-day course (Centers for Disease Control and Prevention et al, 2009).
    3) Adjunctive corticosteroids are recommended in children with moderate-to-severe disease (PaO2 less than 70 mmHg on room air or alveolar-arterial O2 gradient greater than 35 mmHg): Prednisone day 1-5, 1 mg/kg orally twice daily; day 6-10, 0.5 to 1 mg/kg orally twice a day; day 11-21, 0.5 mg/kg orally once daily. Methylprednisolone may be used at 75% of the prednisone dose if IV corticosteroids are necessary (Centers for Disease Control and Prevention et al, 2009a).
    4) 13 YEARS AND OLDER: For HIV-infected adolescents with mild to moderate PCP, a dose of 15 to 20 mg/kg/day (based on trimethoprim component) orally in divided doses every 8 hours or 2 double strength tablets (trimethoprim 320 mg/sulfamethoxazole 1600 mg) orally three times daily for 21 days may be used (Prod Info SEPTRA(R) oral tablets, 2013; Centers for Disease Control and Prevention et al, 2009a).
    5) Adjunctive corticosteroids are recommended in adolescent and adult patients with moderate-to-severe disease (PaO2 less than 70 mmHg on room air or alveolar-arterial O2 gradient greater than 35 mmHg): Prednisone day 1-5, 40 mg orally twice daily; day 6-10, 40 mg orally once a day; day 11-21, 20 mg orally once daily. Methylprednisolone may be used at 75% of the prednisone dose if IV corticosteroids are necessary (Centers for Disease Control and Prevention et al, 2009a).
    2) SHIGELLOSIS
    a) INFANTS LESS THAN 2 MONTHS OF AGE: Contraindicated (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013; Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    b) ORAL TABLETS OR SUSPENSION: 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per day in 2 divided doses for 5 days (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013).
    c) IV: 8 to 10 mg/kg trimethoprim component/day IV in 2 to 4 equally divided doses every 6, 8, or 12 hours for 5 days. MAXIMUM DOSE: 60 mL/day (Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    3) URINARY TRACT INFECTION OR ACUTE OTITIS MEDIA
    a) INFANTS LESS THAN 2 MONTHS OF AGE: Contraindicated (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013; Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).
    b) ORAL TABLETS OR SUSPENSION: 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per day in 2 divided doses for 10 days (Prod Info SEPTRA(R) oral tablets, 2013; Prod Info SEPTRA(R) DS oral double strength tablets, 2013; Prod Info sulfamethoxazole trimethoprim oral suspension, 2013).
    c) IV (URINARY TRACT INFECTION ONLY): 8 to 10 mg/kg trimethoprim component/day IV in 2 to 4 equally divided doses every 6, 8, or 12 hours for up to 14 days. MAXIMUM DOSE: 60 mL/day (Prod Info sulfamethoxazole trimethoprim intravenous injection solution, 2013).

Maximum Tolerated Exposure

    A) ADULT
    1) SUMMARY
    a) Symptoms of overdose that may be life-threatening based on a single dose of trimethoprim and sulfamethoxazole have not been reported (Prod Info SEPTRA(R) oral tablets, 2013).
    2) TRIMETHOPRIM
    a) Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression (Prod Info, 1988).
    b) CASE REPORT: An adult who took 8 g of trimethoprim developed minor symptoms which resolved over 30 hours (Hoppu, 1980).
    c) CASE REPORT: Toxicity was reported in a 35-year-old adult who received 880 mg every 6 hours IV for 11 doses (trimethoprim in combination with sulfamethoxazole) (Personal Communication, 1988).
    3) TRIMETHOPRIM AND SULFAMETHOXAZOLE
    a) CASE REPORT: An iatrogenic overdose of IV trimethoprim/sulfamethoxazole (20 mg/kg/dose of trimethoprim) every 6 hours for 11 doses resulted in agitation, disorientation, and psychosis over 2 days, and a tonic-clonic seizure after 7 doses in a 35-year-old. The white blood cell count and neutrophils reached a nadir of 600 and 300, respectively, 5 days after discontinuation (Personal Communication, 1988).
    b) CASE REPORT: Ingestion of an overdose of 20 tablets (8 g sulfamethoxazole/1.6 g trimethoprim) resulted in an elevated serum creatinine within 48 hours (2.9 mg/dL), and obstruction of the Foley catheter with urine sediment in a 70-year-old man. Lower abdominal pain was also present. Renal function improved by the fourth day (Goff, 1989).
    c) CASE REPORT: A teenager intentionally ingested 20 tablets of propafenone (total 6000 mg) and 24 tablets of trimethoprim-sulfamethoxazole (total 1920 mg and 9600 mg, respectively) and was admitted within an hour and developed a cardiorespiratory arrest shortly after admission. He was rapidly resuscitated. An initial ECG showed bradycardia and a widened QRS of 260 msec with a right bundle branch block. Sinus rhythm and hemodynamic function were rapidly restored with sodium bicarbonate and dopamine. Five hours later, a repeat ECG showed a QRS of 230 msec. Laboratory studies were normal. On day 3, the patient was discharged with a normal ECG and no permanent sequelae. It was suggested that his cardiac arrest was secondary to propafenone toxicity (ie, bradycardia) and QT prolongation was associated with trimethoprim-sulfamethoxazole toxicity (Ardic et al, 2009).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 2010 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 3740 mg/kg (RTECS, 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) Greater than 3 gm/kg (RTECS, 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 1840 mg/kg (RTECS, 2002)
    5) LD50- (ORAL)RAT:
    a) 5350 mg/kg (RTECS, 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) Greater than 3 gm/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Trimethoprim-sulfamethoxazole is a synthetic antibacterial fixed-ratio combination product containing 1 part of trimethoprim to 5 parts of sulfamethoxazole (Prod Info SEPTRA(R) oral tablets, 2013). The combination demonstrates in vitro synergism and is often bactericidal (Reeves et al, 1969).
    B) The sulfonamide, sulfamethoxazole, competes with para-aminobenzoic acid and inhibits bacterial synthesis of dihydrofolic acid. Trimethoprim blocks 2 consecutive steps necessary for the biosynthesis of nucleic acids and proteins essential to many bacteria. This is done by blocking the production of tetrahydrofolic acid from dihydrofolic acid by reversibly inhibiting the required enzyme, dihydrofolate reductase (Prod Info SEPTRA(R) oral tablets, 2013).

Physicochemical

Physical Characteristics

    A) TRIMETHOPRIM - A white to light yellow, odorless, bitter compound (Prod Info Septra(R), trimethoprim and sulfamethoxazole, 2000).
    B) SULFAMETHOXAZOLE - An almost white, odorless, tasteless compound (Prod Info Septra(R), trimethoprim and sulfamethoxazole, 2000).

Molecular Weight

    A) TRIMETHOPRIM - 290.32 (Prod Info Septra(R), trimethoprim and sulfamethoxazole, 2000)
    B) SULFAMETHOXAZOLE - 253.28 (Prod Info Septra(R), trimethoprim and sulfamethoxazole, 2000)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Aboulafia DM: Tremors associated with trimethoprim-sulfamethoxazole therapy in a patient with AIDS: case report and review. Clin Infect Dis 1996; 22:598-600.
    3) Agrawal AK , Chang PP , & Feusner J : Twice weekly Pneumocystis jiroveci pneumonia prophylaxis with trimethoprim-sulfamethoxazole in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2011; 33(1):e1-e4.
    4) Ahn YH & Goldman JM: Trimethoprim-sulfamethoxazole and hyponatremia (letter). Ann Intern Med 1985; 103:161-162.
    5) Ainapurapu B & Kanakadandi UB: Trimethoprim-sulfamethoxazole induced rhabdomyolysis. Am J Ther 2014; 21(3):e78-e79.
    6) Al-Quteimat OM & Al-Badaineh MA: Methotrexate and trimethoprim-sulphamethoxazole: extremely serious and life-threatening combination. J Clin Pharm Ther 2013; 38(3):203-205.
    7) Alappan R, Perazella MA, & Buller GK: Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996; 124:316-320.
    8) Andrade A & Walter C: A rare occurrence of trimethoprim/sulfamethoxazole (TMP/SMX)-induced aseptic meningitis in an older woman (letter). J Am Geriatr Soc 2000; 48(11):1537-1538.
    9) Anon: Co-trimoxazole and blood (editorial). Lancet 1973a; 2:950.
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