Tmp/smx – Bactrim

BACTRIM ® - (trimethoprim /sulfamethoxazole)

Usual Diluents

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Stability / Miscellaneous

Multiples of 80mg/ 125 ml fluid - 6hr stability [ concentration: 0.64 mg/mL]
80mg/100ml - 4hr stability [ concentration: 0.8 mg/mL]
Min dilution - 80 mg/75 ml - 2 hr stability   [ concentration: 1.07 mg/mL]

Example:  375mg/500mL [Conc = 0.75 mg/mL]
Estimated stability ~ 4 hrs (rounding concentration to 0.8 mg/mL)

Label: Do not Refrigerate
Minimum dilution: 80 mg TMP/ 75 ml.

Non-PCP: 10mg/kg/day ( based on TMP component) divided q6h or q8h or q12h.
PCP: 15-20mg/kg/day (based on TMP component) divided q6h.

CLINICAL PHARMACOLOGY
Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N4-acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.

Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The percent of dose excreted in urine over a 12-hour period following the intravenous administration of the first dose of 1200 mg of sulfamethoxazole and 240 mg of trimethoprim on day 1 ranged from 7% to 12.7% as free sulfamethoxazole and 17% to 42.4% as free trimethoprim; and 36.7% to 56% as total (free plus the N4-acetylated metabolite) sulfamethoxazole. When administered together, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum and vaginal fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in breast milk.

Microbiology
Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, this combination blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.

In vitro studies have shown that bacterial resistance develops more slowly with this combination than with either sulfamethoxazole or trimethoprim alone.

In vitro serial dilution tests have shown that the spectrum of antibacterial activity of sulfamethoxazole and trimethoprim injection includes common bacterial pathogens with the exception of Pseudomonas aeruginosa. The following organisms are usually susceptible: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, indole-positive Proteus species including Proteus vulgaris, Haemophilus influenzae (including ampicillin-resistant strains), Streptococcus pneumoniae, Shigella flexneri and Shigella sonnei. It should be noted, however, that there are little clinical data on the use of sulfamethoxazole and trimethoprim injection in serious systemic infections due to Haemophilus influenzae and Streptococcus pneumoniae.

INDICATIONS AND USAGE
Pneumocystis Carinii Pneumonia
Sulfamethoxazole and trimethoprim injection is indicated in the treatment of Pneumocystis carinii pneumonia in children and adults.

Shigellosis
Sulfamethoxazole and trimethoprim injection is indicated in the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei in children and adults.

Urinary Tract Infections
Sulfamethoxazole and trimethoprim injection is indicated in the treatment of severe or complicated urinary tract infections due to susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii and Proteus species when oral administration of sulfamethoxazole and trimethoprim is not feasible and when the organism is not susceptible to single-agent antibacterials effective in the urinary tract.

Although appropriate culture and susceptibility studies should be performed, therapy may be started while awaiting the results of these studies.

CONTRAINDICATIONS
Sulfamethoxazole and trimethoprim are contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole and trimethoprim are also contraindicated in pregnant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Sulfamethoxazole and trimethoprim are contraindicated in infants less than 2 months of age.

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

SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS SMX AND TMP INJECTION, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE SKIN RASH OR ANY SIGN OF ADVERSE REACTION. In rare instances, a skin rash may be followed by more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders. (See package insert for PRECAUTIONS.)

Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice may be early indications of serious reactions.

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

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

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including SMX and TMP injection, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of 'antibiotic-associated colitis'.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration would be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile.

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

Contains benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal.

DOSAGE AND ADMINISTRATION
CONTRAINDICATED IN INFANTS LESS THAN 2 MONTHS OF AGE
CAUTION—SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION MUST BE DILUTED IN 5% DEXTROSE IN WATER SOLUTION PRIOR TO ADMINISTRATION. DO NOT MIX SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION WITH OTHER DRUGS OR SOLUTIONS. RAPID INFUSION OR BOLUS INJECTION MUST BE AVOIDED.

DOSAGE-------------------------
Children and Adults

Pneumocystis Carinii Pneumonia
Total daily dose is 15 to 20 mg/kg (based on the trimethoprim component) given in 3 or 4 equally divided doses every 6 to 8 hours for up to 14 days. One investigator noted that a total daily dose of 10 to 15 mg/kg was sufficient in 10 adult patients with normal renal function.

Severe Urinary Tract Infections And Shigellosis
Total daily dose is 8 to 10 mg/kg (based on the trimethoprim component) given in 2 or 4 equally divided doses every 6, 8 or 12 hours for up to 14 days for severe urinary tract infections and 5 days for shigellosis. The maximum recommended daily dose is 60 mL per day.

For Patients With Impaired Renal Function
When renal function is impaired, a reduced dosage should be employed using the following table:

Renal Dosing -------------------------------------------------------------------------
Package Insert --------------------------------------------------------------
Patients who receive cotrimoxazole intravenously or orally and have impaired renal function should be dosed according to the following dosage schedule:
Creatinine Clearance Dosage (mL/min)

Above 30: Standard regimen
15-30: 1/2 standard regimen
Below 15: Not recommended

Non-PCP:
[>30 ml/min]: no change
[15-30]: 2.5 mg/kg q12h
[<15 ml/min]: not recommended by manufacturer.

Alternative (LESS SUPPORT): 2.5mg/kg q24h (Avoid if possible due to risk of crystalluria/ nephrolithiasis)

PCP:
[>30 ml/min]: no change
[15-30]: 5mg/kg q12h
[<15 ml/min]: not recommended by manufacturer.

Alternative (LESS SUPPORT): 5mg/kg q24h (Avoid if possible due to risk of crystalluria/ nephrolithiasis)

Hemodialysis:
Not recommended by manufacturer.
Alternative (LESS SUPPORT):
Oral: Avoid if possible. If unavoidable, give one SS/DS q24h.
IV: Avoid if possible. If unavoidable, give 5mg/kg q24h.

------------Micromedex --------------------------------------------------------------
Guidelines for the administration of cotrimoxazole (based on the trimethoprim component) in patients with renal dysfunctions (Paap & Nahata, 1995; Paap & Nahata, 1989):

INDICATION/RENAL FUNCTION DOSE
PCP TREATMENT
CrCl > than 30 ml/min
15-20 mg/kg/day divided q6-8h

CrCl 15 to 30 ml/min
15-20 mg/kg/day divided q6-8h for 48h then 7-10 mg/kg/day divided q12h

CrCl < 15 ml/min
15-20 mg/kg/dose q48h (or 7-10 mg/kg/day divided q12-24h)

Hemodialysis
15-20 mg/kg/dose before dialysis and 7-10 mg/kg/dose after dialysis

PCP PROPHYLAXIS
CrCl > 30 ml/min
5 mg/kg q24h for 3 to 7 doses/week

CrCl 15 to 30 ml/min
5 mg/kg q24-48h for 3 to 7 doses/week

CrCl < 15 ml/min
5 mg/kg q48-72h

Hemodialysis
5 mg/kg after dialysis

OTHER INFECTIONS
CrCl greater than 30 ml/min
8-12 mg/kg/day divided q12h for 14 days then 4-6 mg/kg q24h

CrCl 15 to 30 ml/min
8-12 mg/kg/day divided q12h for 1-2 days then 4-6 mg/kg/day q24h

CrCl less than 15 ml/min
8-12 mg/kg/dose q48h (or 4-6 mg/kg/day divided q12-24h)

Hemodialysis
8-12 mg/kg/dose before dialysis and 4-6 mg/kg/dose after dialysis

Method Of Preparation
Sulfamethoxazole and trimethoprim injection must be diluted. EACH 5 ML SHOULD BE ADDED TO 125 ML OF 5% DEXTROSE IN WATER. After diluting with 5% dextrose in water the solution should not be refrigerated and should be used within 6 hours. If a dilution of 5 mL per 100 mL of 5% dextrose in water is desired, it should be used within 4 hours. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.

Multidose Vials
After initial entry into the vial, the remaining contents must be used within 48 hours.

The following infusion systems have been tested and found satisfactory: unit-dose glass containers; unit-dose polyvinyl chloride and polyolefin containers. No other systems have been tested and therefore no others can be recommended.

Dilution
EACH 5 ML OF SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION SHOULD BE ADDED TO 125 ML OF 5% DEXTROSE IN WATER.

Note: In those instances where fluid restriction is desirable, each 5 mL may be added to 75 mL of 5% dextrose in water. Under these circumstances the solution should be mixed just prior to use and should be administered within 2 hours. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.

DO NOT MIX SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION 5% DEXTROSE IN WATER WITH DRUGS OR SOLUTIONS IN THE SAME CONTAINER.

Administration
The solution should be given by intravenous infusion over a period of 60 to 90 minutes. Rapid infusion or bolus injection must be avoided. Sulfamethoxazole and trimethoprim injection should not be given intramuscularly.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

HOW SUPPLIED

5 mL single dose amber vials packaged 10 per shelf pack.
10 mL multiple dose amber vials packaged 10 per shelf pack.
30 mL multiple dose amber vials packaged individually.

STORE AT ROOM TEMPERATURE 15°–30° C (59°–86° F).
DO NOT REFRIGERATE

Reference:
Teva Parenteral Medicines, Inc. Package Insert: SULFAMETHOXAZOLE, AND TRIMETHOPRIM (sulfamethoxazole and trimethoprim) injection. Revised: 10/2009. Accessed: July 2010.