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Co-trimoxazole (trimethoprim and sulfamethoxazole) parenteral

Presentation

Concentrate for solution for infusion containing 80 mg trimethoprim with 400 mg sulfamethoxazole (co-trimoxazole) in each 5 ml.

Drugs List

  • co-trimoxazole (trimethoprim 80mg/5ml and sulfamethoxazole 400mg/5ml) concentrate for solution for infusion
  • Therapeutic Indications

    Uses

    Pneumocystis jirovecii: prophylaxis
    Pneumocystis jirovecii: treatment
    Susceptible acute or chronic bronchitis only if this drug essential
    Susceptible urinary tract infections only if this drug essential
    Toxoplasmosis: prophylaxis
    Toxoplasmosis: treatment
    Treatment of nocardial infections
    Treatment of otitis media only if this drug essential

    Acute uncomplicated urinary tract infection
    Treatment of Pneumocystis jiroveci pneumonitis
    Prophylaxis of Pneumocystis jiroveci pneumonitis
    Treatment of toxoplasmosis
    Prophylaxis of toxoplasmosis
    Treatment of nocardiosis

    Co-trimoxazole infusion should only be used when oral therapy is unacceptable, when initiation of therapy is particularly urgent or for convenience in patients already receiving intravenous fluids.

    Co-trimoxazole should only be used where, in the judgement of the physician, the benefits of this combination treatment outweigh any possible risks and only when preferable to using a single agent.

    Dosage

    Adults

    Acute infections
    160mg trimethoprim + 800mg sulfamethoxazole every 12 hours. This may be increased to 240mg trimethoprim + 1200mg sulfamethoxazole every 12 hours in severe infections.
    Treatment should be continued until patients are symptom free for two days.

    Treatment of Pneumocystis jiroveci pneumonitis
    20mg trimethoprim + 100mg sulfamethoxazole per kilogram bodyweight per day in two or more divided doses.
    Change to oral therapy as soon as possible and continue for a total treatment period of two weeks.
    The aim is to obtain peak plasma or serum levels of trimethoprim of equal to or greater than 5microgram/ml (verified in patients receiving 1-hour infusions of intravenous co-trimoxazole).

    Prophylaxis of Pneumocystis jiroveci pneumonitis
    160mg trimethoprim + 800mg sulfamethoxazole every 12 hours for the duration of risk.

    Treatment of nocardiosis
    There is no consensus on the most appropriate dosage. The decision should be based on clinical experience.

    Treatment and prophylaxis of toxoplasmosis
    There is no consensus on the most appropriate dosage. The decision should be based on clinical experience.
    The manufacturer suggests that the doses for Pneumocystis jiroveci pneumonitis prophylaxis may be appropriate.

    Children

    Acute infections
    The recommended dosage is approximately 6mg trimethoprim + 30mg sulfamethoxazole per kilogram bodyweight per 24 hours, given in two equally divided doses. For severe infections in all age groups, dosage may be increased by 50%. The following schedule may be used as a guide:
    Children aged 12 years to 18 years
    (See Dosage; Adult).
    Children aged 6 years to 12 years
    80mg trimethoprim + 400mg sulfamethoxazole every 12 hours.
    Children aged 6 months to 5 years
    40mg trimethoprim + 200mg sulfamethoxazole every 12 hours.
    Children aged 6 weeks to 5 months
    20mg trimethoprim + 100mg sulfamethoxazole every 12 hours.

    Treatment should be continued until patients are symptom free for two days.

    Treatment of Pneumocystis jiroveci pneumonitis
    20mg trimethoprim + 100mg sulfamethoxazole per kilogram bodyweight per day in two or more divided doses.
    Change to oral therapy as soon as possible and continue for a total treatment period of two weeks.
    The aim is to obtain peak plasma or serum levels of trimethoprim of equal to or greater than 5microgram/ml (verified in patients receiving 1-hour infusions of intravenous co-trimoxazole).

    Patients with Renal Impairment

    Patients over 12 years of age

    Creatinine clearance greater than 30ml/minute
    (See Dosage; Adult).
    Creatinine clearance 15 to 30ml/minute
    Administer half the standard adult dosage.

    The Renal Drug Handbook suggests the following doses
    Glomerular filtration rate 30 to 50ml/minute
    (See Dosage; Adult)
    Glomerular filtration rate 15 to 30ml/minute
    Administer half the standard adult dosage.
    For the treatment of Pneumocystis jiroveci pneumonia: 60mg/kg twice daily for three days then 30mg/kg twice daily
    Glomerular filtration rate less than 15ml/minute
    Administer half the standard adult dosage.
    For the treatment of Pneumocystis jiroveci pneumonia: 30mg/kg twice daily.This should only be given if haemodialysis facilities are available.

    Measurements of plasma concentration of sulfamethoxazole at intervals of two to three days are recommended in samples obtained 12 hours after administration. If the concentration of total sulfamethoxazole exceeds 150microgram/ml then treatment should be interrupted until the value falls below 120microgram/ml.

    Administration

    Following dilution, administer by intravenous infusion over approximately one to one and a half hours. This should be balanced against the fluid requirements of the patient.
    When fluid restriction is necessary, co-trimoxazole infusion may be administered at a higher concentration. Consider 5 ml diluted with 75 ml of Glucose 5% w/v in water and infused over a period not exceeding one hour.

    Contraindications

    Children under 6 weeks - if for the treatment of acute infection
    Neonates under 4 weeks - if for the prophylaxis of pneumocystis pneumonia
    Neonates under 4 weeks - if for the treatment of pneumocystis pneumonia
    Acute porphyria
    Renal impairment - creatinine clearance below 15ml/minute
    Severe hepatic impairment

    Precautions and Warnings

    Allergic disposition
    Cardiopulmonary disorder
    Elderly
    Alcoholism
    Asthma
    Breastfeeding
    Epileptic disorder
    Folate deficiency
    G6PD deficiency
    Hyperkalaemia
    Malnutrition
    Mild hepatic impairment
    Pregnancy
    Renal impairment - creatinine clearance 15-29ml/minute
    Severe haematological disorder

    Do not use in the treatment of streptococcal pharyngitis
    Reduce dose in patients with renal impairment
    Sodium content of formulation may be significant
    Advise ability to drive/operate machinery may be affected by side effects
    Cross sensitivity to sulfonamides and derivatives may occur
    Folate supplementation may be necessary in some patients
    Contains alcohol
    Contains sodium metabisulfite. Caution,may cause allergic reactions
    Contains sulfite. Discontinue if hypersensitivity reactions occur
    Some formulations contain propylene glycol
    Must be diluted before use
    Maintain hydration and urinary output
    Monitor for signs of bone marrow depression
    Monitor plasma levels and adapt dose in patients with renal impairment
    Monitor plasma potassium in patients at risk of hyperkalaemia
    Monitor plasma sodium in patients at risk of hyponatraemia
    Perform blood counts in patients with alcohol dependence
    Perform blood counts on prolonged use of this treatment
    Discontinue treatment if Stevens-Johnson Syndrome suspected
    Discontinue treatment if toxic epidermal necrolysis is suspected
    Superinfection may occur during therapy
    Discontinue if blood dyscrasia develops
    Discontinue treatment if rash occurs
    Advise patients to report skin rash

    If the patient has developed Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of co-trimoxazole, co-trimoxazole must not be re-started in this patient at any time.

    Monitor blood counts monthly in patients on long-term treatment as asymptomatic changes may occur due to the lack of available folate. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with antibacterial activity. Blood counts should also be taken in patients who are predisposed to folate deficiency.

    It is essential to maintain an adequate fluid intake and urinary output. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. Patients suffering from malnutrition may be at increased risk of crystalluria.

    Fluid overload is possible, especially when very high doses are being administered to patients with underlying cardiopulmonary disease.

    Use with caution in patients with severe allergy or bronchial asthma. Sulfonamides may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible individuals. Co-trimoxazole infusion contains sodium metabisuphite, which may rarely cause severe hypersensitivity reaction and bronchospasm.

    Trimethoprim has been noted to impair phenylalanine metabolism but this is of no clinical significance in phenylketonuric patients on appropriate dietary restriction.

    Co-trimoxazole infusion contains ethanol, up to 521 mg per dose (13.2 vol%). This is harmful for those suffering from alcoholism and needs to be taken into account in pregnant or breastfeeding women, children and high-risk groups such as patients with liver disease or epilepsy.

    Co-trimoxazole infusion contains 1.7 mmoles (or 38.87 mg) of sodium which needs to be taken into consideration by patients on a sodium controlled diet.

    Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of Pneumocystis jiroveci pneumonitis.

    The administration of co-trimoxazole to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulfonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

    Pregnancy and Lactation

    Pregnancy

    Co-trimoxazole is contraindicated in pregnancy, especially during the first trimester, unless the potential benefit to the mother outweighs the potential risk to the foetus.

    Trimethoprim and sulfamethoxazole cross the placenta (Briggs, 2015).

    Trimethoprim is a folate antagonist. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans. Defects associated with trimethoprim include cardiovascular defects, neural tube defects and possibly oral clefts. Folic acid supplementation (at least 0.4 mg per day) started before conception, or concurrently with trimethoprim, may decrease the risk of congenital defects (Briggs, 2015).

    Sulfamethoxazole competes with bilirubin for binding to plasma albumin. If co-trimoxazole is administered close to the delivery, hyperbilirubinaemia and associated kernicterus may occur in the neonate. This theoretical risk is more likely in infants at an increased risk of hyperbilirubinaemia, such as preterm babies and those with glucose-6-phosphate dehydrogenase deficiency.

    In animal studies, both agents have been shown to cause foetal abnormalities. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses. At doses in excess of recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats.

    Schaefer (2007) concludes that co-trimoxazole may be a safe alternative drug for antibiotic treatment of urinary tract infections when penicillins and cephalosporins are ineffective.

    The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

    Lactation

    Use co-trimoxazole with caution in breastfeeding.

    Trimethoprim and sulfamethoxazole are excreted into breast milk.

    Co-trimoxazole infusion should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. Additionally, administration of co-trimoxazole for infusion should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

    Schaefer (2007) indicates that co-trimoxazole can be used during breastfeeding for the appropriate indications. Briggs (2015) suggests that although both agents are excreted into breast milk there is no significant risk to a healthy, full term neonate, however sulfonamides should be avoided in ill, stressed or premature infants, infants with hyperbilirubinaemia or glucose-6-phosphate dehydrogenase deficiency.

    Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
    Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

    Side Effects

    Agranulocytosis
    Allergic myocarditis
    Anaphylaxis
    Angioedema
    Anorexia
    Antibiotic-associated colitis
    Aplastic anaemia
    Arthralgia
    Aseptic meningitis
    Ataxia
    Blood dyscrasias
    Bone marrow depression
    Cholestatic jaundice
    Convulsions
    Cough
    Crystalluria
    Depression
    Diarrhoea
    Dizziness
    Drug fever
    Eosinophilia
    Erythema multiforme
    Exfoliative dermatitis
    Fever
    Fixed drug eruption
    Fluid overload
    Glossitis
    Haemolysis
    Haemolytic anaemia
    Hallucinations
    Headache
    Hepatic impairment
    Hepatic necrosis
    Hyperkalaemia
    Hypersensitivity reactions
    Hypoglycaemia
    Hyponatraemia
    Increase of liver transaminases
    Interstitial nephritis
    Jaundice
    Leucopenia
    Local pain (injection site)
    Megaloblastic anaemia
    Methaemoglobinaemia
    Moniliasis
    Myalgia
    Myocarditis
    Nausea
    Neutropenia
    Pancreatitis
    Periarteritis nodosa
    Peripheral neuritis
    Peripheral neuropathy
    Phlebitis (injection site)
    Photosensitivity
    Pseudomembranous colitis
    Pulmonary infiltrates
    Purpura
    Rash
    Renal failure
    Renal impairment
    Respiratory tract allergic reaction
    Rhabdomyolysis
    Serum bilirubin increased
    Serum sickness
    Severe cutaneous adverse reactions
    Shortness of breath
    Stevens-Johnson syndrome
    Stomatitis
    Systemic lupus erythematosus
    Thrombocytopenia
    Tinnitus
    Toxic epidermal necrolysis
    Uveitis
    Vasculitis
    Vasculitis (allergic)
    Vertigo
    Vomiting

    Overdosage

    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

    Further Information

    Last Full Review Date: October 2016

    Reference Sources

    Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

    Summary of Product Characteristics: Co-Trimoxazole for infusion 16 mg/ 80mg per ml. Aspen. Revised November 2015.

    The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.

    NICE Evidence Services Available at: www.nice.org.uk Last accessed: 07 September 2017

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