Principles of anti-microbial treatments, Sulphonamides/Trimethoprim and anti-fungal agents Flashcards
List the 15 principles of the treatment using anti-microbial drugs.
- It is important to decide wether the patient even requires anti-microbial therapy.
- Deciding which anti-microbial drug to use – in some infections the choice is made clear immediately after establishing diagnosis (the causative agent is always the same and its antibiotic susceptibility is known). In others the m.o. remains unidentified, in which case we rely on “empirical therapy” (treatment is undertaken based upon educated guesses).
- The following 3 things should be taken into consideration when choosing a drug: severity of the infection, immunological status of the patient, drug cost.
- Early therapy is most effective therapy.
- Effective/Sufficient high doses are recommended, as low daily doses often lead to microbial
resistance (Lower rate of drug effect gives more time for microbes to retaliate). - Parenteral administration is preferred in cases of emergency, vomiting, inadequate oral
absorption or when patient is unconscious. - Antimicrobial therapy should not be discontinued or changed without reason.
- Two or more antibiotics should not be combined without good reason.
- Combined antimicrobial therapy is required (give reasons).
- In cases of recurring infections antimicrobials should be combined with immunostimulants (for effective immune response).
- Any factors, complicating treatment should be removed.
- In renal/liver impairment the daily dose should be adjusted, careful monitoring of plasma drug concentrations in patient.
- Antimicrobial treatment should continue three days after clinical recovery.
- Antibiotic prophylaxis is required in (give reasons).
- The attending physician should be well acquainted with the pharmacology and toxicology of antimicrobial drug as well as its possible adverse reactions.
Explain the action of the Sulfonamide drugs (Folate antagonists)
Sulfonamides are a group of anti-biotics that function to inhibit the “de novo” formation of dihydrofolic acid within bacteria, via inhibition of the enzyme that forms dihydrofoli acid “Dihydropteroate synthase”. “Trimethoprim” is another type of folate antagonist, but instead of competing with PABA for the formation of dihydrofolic acid, it instead prevents the conversion of dihydrofolate into the active form “Tetrahydrofolic acid” via inhibition of “dihydrofolate reductase”. The lack of folic acid within the bacteria has a effect of reduced DNA synthesis and reduced cell growth. (Many bacteria rely on de novo synthesis as they are impermeable to the environmental folate, some are permeable). Examples of sulfonamides include “Sulfadiazine”, “Sulfadiazine” and “Sulfamethoxazole”.
The bacteria may develop resistance against the sulfonamide agents via random DNA mutation or plasmid transfers. Other methods of resistance are:
- Increased PABA concentration
- Altered dihydropteroate synthase enzyme
- Decreased cellular permeability to sulfa drugs
Explain the pharmacology of the sulfonamides? (Administration, distribution, metabolism, excretion and adverse effects).
Administration: Genrerally good oral absorption, except for sulfasalazine, which is used for treatment IBD’s. IV administration of sulfonamides are used for emergancy situations and severe infection. They arent applied topically due to the risk of “sensitization” (increase in a drug effect upon successive exposures to a drug). Silver sulfur diazine is topically applied in burn wards for reducing burn associated sepsis (over reaction to an infection).
Distribution: Highly bound to albumin hence have wide distribution with CSF/PBP penetration.
Metabolism: Occurs via acetylation/conjugation into inactive products that have no anti-microbial activity. However these inactive prodcuts have can be toxic and lead to “Crystalluria” (Stone formation in kidney) - due to precipitation of inactive metabolite at neutral and acidic PH. –> Kidney damage.
Elimination: glomerular filtration and secretions (breast milk).
Adverse drugs reactions:
1. Warfarin potentiation: Sulfamethoxazole functions to displace warfarin from albumin, causing its accumulation in the plasma. Blockage of its hepatic isoenzyme “CYP2C9”, reduced metabolism and removal of warfarin.
- Crystalluria : Can be avoided by adequate hydration and keeping condition alkaline to prevent precipitation of the inactive metabolite.
- Haemolytic anaemia: Due to glucose-6-phosphate DH deficiency.
- Kernicterus: Sulfa drugs cause displacement of bilrubin from binding sites, causing accumliation in the brain (bilrubin associated brain damage).
- Hypersensitivity: Steven-johnson syndrome for example.
Explain Trimethoprim?
Trimethoprim is a potent inhibitor of dihydrofolate reductase, preventing conversion of dihydrofolic acid into active drug form “tetrahydrofolic acid”. It is primary used in combination with sulfamethoxazole (COTRIMOXAZOLE) for the treatment of UTI’s and bacterial prostatitis.
Resistance mechanisms are similar but slightly different to the sulfonamides:
- Altered dihydrofolate reductase
- Reduced cellular permeability to the drug
- Presence of efflux pump which export trimethoprim on entry.
Pharmacokinetics: Good oral absorption, accumulates well in the acidic prostatic and vaginal fluid due to its basic nature. Wide distribution as it has the ability to penetrate the CSF, renal excretion unchanged.
Adverse effects: Stimulates the effects of folic acid deficiency (Megaloblastic anaemia, granulocytopenia and leukopenia).
Explain the “anti-fungal” drugs.
These drugs are divided into those that treat “Subcutanous/systemic mycotic infections” and “cutaneous mycotic infections. They target the components of the fungi such as the “chitin” that make up their cell walls, fungal cell membranes comprise of “ergosterol” rather than cholesterol.
Subcutaneous and systemic drugs:
- Amphotericin B
- Anti-metabolite anti fungals
- Azole anti-fungals
- Fluconazol
- Itraconazol
- Voriconazol
Drugs for cutaneous mycotic infections (Imidazoles)
Explain the pharmacology of the systemic/subcutaneous anti-fungal drugs?
- Amphotericin B: Functions to target ergosterol in the fungal cell membranes, which creates pores, causing cell leakage and cell death. Pharmacology: Slow IV infusion, highly protein bound hence wide distribution, primarily renal excretion. “Feeling really hot today” is pneumonic for adverse effects: Fever, renal impairment, hypotension and thrombophlebitis. Resistance is due to reduced ergosterol in cell membrane.
- Anti-metabolite antifungals: “FLUCYTOSINE” is converted to 5-fluorouracil which disrupts protein synthesis in the fungal cells. Resistance aims at any of the enzymes being affected in the conversion process. This resistance can be reduced if the anti-metabolite anti fungal is used in combination with another anti fungal drug. Good oral absorption, wide distribution and penetration into CSF. Excretion via glomerular filtration. Adverse effects of Flucystosine is thrombocytopenia, neutropenia and bone marrow depression.
- Azole anti-fungals: Comprised of “imidiazoles” and “triazoles”. Imidiazoles are applied topically for the treatment of cutanneous fungla infections, whereas triazoles are used for systemic and cutaneous mycotic infections. The triazole anti-fungals include fluconazole, itraconazole and voriconazole. The MOA of these agents is they disturb the conversion of lanosterol –> ergosterol, inhibiting cell membrane formation, fungal cell growth. This is achieved through the inhibition of “14 alpha demethylase. There are 3 mechanisms of resistance against azole anti-fungals: reduced ergosterol content, mutations of 14 alpha demethylase and efflux pumps. They are considered to be teratogenic, should be avoided in pregnancy.
Triazoles are administered orally (for systemic mycoses); good absorption, good distribution, metabolised in the liver, excretion with urine; ADRs – GIT disturbances, hepatotoxicity, hematotoxicity, hormonal changes – menstrual disturbances, gynecomastia, sexual dysfunction.
