PMS-Polytrimethoprim

PMS-Polytrimethoprim Uses, Dosage, Side Effects, Food Interaction and all others data.

Polymyxin B Sulfate is the Sulfate salt of Polymyxins B1 & B2, which are produced by the growth of Bacillus polymyxa. Polymyxin B Sulfate has a bactericidal action against almost all Gram negative bacilli. Polymyxins increase the permeability of the bacterial cell membrane leading to death of the cell.

Polymyxin B is an antibiotic that disrupts the outer cell membrane of Gram negative bacteria, binds and neutralizes lipopolysaccharide, and inhibits respiration of Gram-negative bacterial cells. Polymyxin B can be given by a number of routes to treat susceptible Gram negative bacterial infections. Absorption of the drug is poor (though not necessary for most of its activity) and the excreted drug is unchanged by metabolic processes. Polymyxin B is generally indicated for susceptible Gram negative infections of the urinary tract, meninges, and blood stream.

Trimethoprim, a diaminopyrimidine, is a reversible inhibitor of dihydrofolate reductase. It inhibits the conversion of bacterial dihydrofolic acid to tetrahydrofolic acid necessary for the synthesis of nucleic acids and proteins. It is either bacteriostatic or bacteriocidal, acting on the same metabolic pathway as sulfonamides.

Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative Staphylococcus species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy.

As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

PMS-Polytrimethoprim
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	PMS-Polytrimethoprim
Generic	trimethoprim + polymyxin b
Type	Ophthalmic
Therapeutic Class
Manufacturer
Available Country	Canada, United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Acute infections caused by susceptible strains of Pseudomonas aeruginosa:

Polymyxin B Sulfate is a drug of choice in the treatment of infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of Pseudomonas aeruginosa.

It may be used for serious infections caused by susceptible strains of the following organisms, when less potentially toxic drugs are ineffective or contraused:

H. influenzae: Specifically meningeal infections
Escherichia coli: Specifically urinary tract infections
Aerobacter aerogenes: Specifically bacteremia
Klebsiella pneumoniae: Specifically bacteremia

For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of the following organisms: Escherichiacoli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species and coagulase-negative Staphylococcus species, including S. saprophyticus.

Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to trimethoprim. Therapy may be initiated prior to obtaining the results of these tests.

How PMS-Polytrimethoprim works

The alpha and gamma diaminobutyric acid of a positively charged polymyxin B forms an electrostatic interaction with the phosphate groups of a negatively charged lipid A on the outer membrane of a Gram negative bacterium. Calcium and Magnesium ions are displaced from phosphates of the membrane lipids, destabalising the lipopolysaccharide (LPS), increasing membrane permeability, causing cytoplasmic leaking, and killing the cell.

Polymyxin B can also bind and neutralize LPS released during bacterial lysis, preventing reactions to endotoxin.

A third activity of polymyxin B is the inhibition of type II NADH-quinone oxidoreductases in the bacterial inner membrane, which are essential for respiration.

Polymyxin is active against common Gram negative bacteria but not Gram negative cocci, Gram positive bacteria, or anaerobic bacteria.

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes.

Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity.

Dosage

PMS-Polytrimethoprim dosage

Intravenous: Dissolve Polymyxin B 500,000 units in 300 to 500 ml solutions for parenteral Dextrose injection 5% for continuous drip.

Intramuscular: Dissolve Polymyxin B 500,000 units in 2 ml 0.9% Sodium Chloride solution. It is not recommended routinely because of severe pain at injection site, particularly in infants and children.

Intrathecal: Dissolve Polymyxin B 500,000 units in 10 ml 0.9% Sodium Chloride solution for 50,000 units per ml dosage unit.

In meningeal infections, Polymyxin B Sulfate should be administered only by the intrathecal route.

For IV route:

Adult & Children (Normal kidney function): Dose (Units/kg/day) is 15,000-25,000(Not exceed 25,000) and Dosage frequency/Duration is infusions may be given every 12 hours over a period of approximately 60 to 90 minutes.
Adult & Children (Renal impairment): Dose (Units/kg/day) is Less than 15,000 and Dosage frequency/Duration is Infusions may be given every 12 hours over a period of approximately 60 to 90 minutes.
Infants (Normal kidney function): Dose (Units/kg/day) is Maximum 40,000

For IM route:

Adult & Children: Dose (Units/kg/day) is 25,000-30,000 and Dosage frequency/Duration is Dose should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals.
Infants (Normal kidney function): Dose (Units/kg/day) is Maximum 40,000

For Intrathecal:

Children under 2 years of age: Dosage frequency/Duration is 20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day. Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.
Adults and children over 2 years of age: 50,000 units once daily for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

The usual oral adult dosage is 100 mg of trimethoprim every 12 hours or 200 mg trimethoprim every 24 hours, each for 10 days.

The use of trimethoprim in patients with acreatinineclearance of less than 15 ml/min is not recommended.

For patients with a creatinine clearance of 15 to 30 ml/min, the dose should be 50 mg every 12 hours

Side Effects

Clostridium difficile associated diarrhea has been reported with use of Polymyxin B. Nephrotixic reactions: Albuminuria, cylinduria, azotemia, and rising blood levels, Neurotoxic reactions: Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral aresthesias (circumoral and stocking glove), apnea due to concurrent use of curariform muscle relaxants, other neurotoxic drugs or inadvertent overdosage, and signs of meningeal irritation with intrathecal administration, e.g., fever, headache, stiff neck. Other reactions occasionally reported: Drug fever, urticaria rash, severe pain at IM injections sites and thrombophelbitis at IV injections sites.

Pruritus, rash, urticaria, mild GI disturbance (e.g. nausea, vomiting, glossitis, sore mouth); disturbance of liver enzymes, photosensitivity, angioedema, myalgia, headache; hyperkalaemia, hyponatraemia; agranulocytosis. Rarely, fever, cholestatic jaundice, exfoliative dermatitis, anaphylaxis, aseptic meningitis, megaloblastic anaemia, thrombocytopenia, leucopenia, neutropenia, methaemoglobinaemia.

Toxicity

Nephrotoxicity can occur in patients as polymyxin B is thought to accumulate in renal cells after renal tubular reabsorption. This accumulation can lead to apoptosis of renal cells and decrease in renal function. In recent studies, acute kidney injury (AKI) has been seen in 31.3% to 39.4% of patients receiving polymyxin B.

Overdose cases can cause neuromuscular block leading to apnea, muscular weakness, vertigo, transient facial parasthesia, slurred speed, vasomotor instability, visual disturbance, confusion, psychosis, and respiratory arrest. Renal failure has also been seen through decreased urine output, and increased serum concentrations of blood urea nitrogen.

Overdose of polymyxin B is treated by stopping the drug and beginning symptomatic treatment. Intravenous administration of mannitol may enhance renal clearance, and hemodialysis may manage renal complications.

Safety of polymyxin B has not been established in pregnancy, breast feeding, pediatrics, and geriatrics. Polymyxin B should no be used in pregnancy unless the benefit outweighs the risk. Nursing mothers should either stop nursing or stop polymyxin B treatment depending on the risks to both the mother and child. Pediatric patients should be frequently monitored for renal function and no dosing information is available in children under 2 years of age. Geriatric patients should have renal function assessed before and regularly during therapy.

The oral LD₅₀ in mice and rats is 2764 mg/kg and >5300 mg/kg, respectively.

Prescribing information for trimethoprim states that signs of overdose may be evident following ingestion of doses >1 gram, and may include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression. Treatment should consist of general supportive measures and gastric lavage, if applicable. Urinary acidification may increase renal elimination of trimethoprim. Hemodialysis is only moderately effective in eliminating trimethoprim and peritoneal dialysis is of no benefit.

Precaution

Baseline renal function should be done prior to therapy, with frequent monitoring of renal function and blood levels of the drug during parenteral therapy.

Patient with actual or potential folate deficiency (e.g. malnourished, chronic anticonvulsant therapy, elderly). Hepatic and renal impairment. Childn (esp those with fragile X chromosome associated with mental retardation). Pregnancy and lactation.

Interaction

The concurrent or sequential use of other neurotoxic and/or nephrotox-ic drugs with Polymyxin B sulfate, particularly bacitracin, kanamycin, streptomycin, tobramycin, amikacin, cephaloridine, cephalothin, paromycin, polymyxin E (colistin), neomycin, gentamicin, and vancomycin, Bumetanide, celecoxib, cisplatin, cyclosporine, diclofenac, misoprostol, diphenhydramine, ibuprofen, naproxen, esomeprazole, etodolac, general anesthetic, gentamycin, ketorolac, meloxicam, tenofovir etc should be avoided.

May increase concentration of dapsone. Increased elimination and shortened elimination half-life with rifampicin. Increases concentration of phenytoin, digoxin, procainamide, rosiglitazone, repaglinide, zidovudine, zalcitabine, lamivudine. Increased risk of nephrotoxicity with ciclosporin. Potentiates anticoagulant effect of warfarin. May cause hyponatraemia with diuretics. May cause megaloblastic anaemia with other folate inhibitors (e.g. pyrimethamine, methotrexate). May increase potential for bone marrow aplasia with bone barrow depressants. Increased risk of hyperkalaemia with ACE inhibitors.

Volume of Distribution

1 compartment models estimate the volume of distribution to be 34.3L to 47.2L. However, the general consensus is that the volume of distribution is yet to be determined.

Trimethoprim is extensively distributed into various tissues following oral administration. It distributes well into sputum, middle ear fluid, and bronchial secretions. Trimethoprim distributes efficiently into vaginal fluids, with observed concentrations approximately 1.6-fold higher than those seen in the serum. It may pass the placental barrier and into breast milk. Trimethoprim is also sufficiently excreted in the feces to markedly reduce and/or eliminate trimethoprim-susceptible fecal flora.

Elimination Route

Administration by the oral route does not lead to absorption.

Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (C_max) are achieved within 1 to 4 hours (T_max) following the administration of a single 100mg dose. Trimethoprim appears to follow first-order pharmacokinetics, as a single 200mg dose results in serum concentrations approximately double that of a 100mg dose. The steady-state AUC of orally administered trimethoprim is approximately 30 mg/L·h.

Half Life

In one study the half life was 9 to 11.5 hours. However, a Canadian monograph states the half life to be 6 hours, and 48-72 hours in patients with renal insufficiency.

Trimethoprim half-life ranges from 8-10 hours, but may be prolonged in patients with renal dysfunction.

Clearance

1 compartment models estimate clearance to be 2.37L/h to 2.5L/h.

Following oral administration, the renal clearance of trimethoprim has been variably reported between 51.7 - 91.3 mL/min.

Elimination Route

Polymyxin B is proposed to be primarily eliminated through renal tubular reabsorption and non-renal pathways. Urine collection in humans and animals show 1. However, a Canadian product monograph states the drug is primarily eliminated through the kidneys and that 60% of polymyxin B is recovered in the urine. This discrepancy can be explained by the 12 to 24 hour lag time between administration and significant elimination of polymyxin B. Non-renal elimination is not well understood but all 4 components of polymyxin B have been detected in bile.

Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of which is unchanged parent drug.

Pregnancy & Breastfeeding use

There are no controlled data in human pregnancy. Safety has not been established during pregnancy. There is no recommendation regarding use during lactation. There is no study on whether it is secreted with human milk.

Pregnancy Category C. Trimethoprim has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.

Nursing Mothers: Trimethoprim is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism, caution should be exercised when trimethoprim is administered to a nursing woman.

Contraindication

Hypersensitivity. Blood dyscrasias (e.g. megaloblastic anaemia).

Special Warning

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of Trimethoprim as a single agent has not been established in pediatric patients under 12 years of age.

Geriatric Use: Clinical studies of Trimethoprim tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been published. Trimethoprim is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor potassium concentrations and to monitor renal function by calculating creatinine clearance.

Acute Overdose

Polymyxin-induced toxicity associated with overdose has been reported. Overdose of Polymyxin can result in neuromuscular blockade, which can lead to apnea, muscular weakness, vertigo, transient facial paresthesia, slurred speech, vasomotor instability, visual disturbance, confusion, psychosis and possible respiratory arrest. Overdose can also cause renal failure characterized by decreased urine output and increased serum concentrations of BUN and creatinine. There is no specific antidote for Polymyxin B Sulfate overdose. In case of Polymyxin B Sulfate overdose, the drug should be stopped and symptomatic treatment instituted. Quick diuresis by IV administered mannitol may help to enhance renal clearance of the drug and thus to reduce serum drug levels. Hemodialysis or peritoneal dialysis may help in order to manage renal complications.

Symptoms: Nausea, vomiting, dizziness, headache, mental depression, confusion, bone marrow depression (e.g. thrombocytopenia, leucopenia, megaloblastic anaemia).

Management: Symptomatic and supportive treatment. May employ gastric lavage and forced diuresis. Enhance elimination through urine acidification. May administer Ca folinate (5-15 mg daily) if bone marrow depression occurs.

Storage Condition

Before reconstitution, do not store above 30°C; and keep away from light and out of the reach of children. After reconstitution or dilution, unused portion must be stored at 2° to 8°C and should be discarded after 72 hours if not used.

Store between 15-25˚C. Protect from light