Fungal infection ,Antifungals agents and antibacterial agent eg:curam-LAW JIA JUIN

BY LAW JIA JUIN

A Statement from author:Today I am going to make my article into points form, because I heard from some readers that my previous articles are too long and hard to be understood. And I myself also find out that reading an article of few hundreds word can be very tired.

B Background: My uncle had asked me what antifungal to be applied for fungal infection.

C Types of microorganism:

•         Fungi/fungus

•         Archae

•          Bacteria

•          Algae

•         Protozoa

•          Viruses

•          Prions

D So…what is fungus and what properties it has?

1.      A fungus is a group of eukaryotic organisms which involves microorganisms such as yeasts and molds ,as well as larger microorganism like mushroom.  <Read also extra info for comparison between prokaryotic organism and eukaryotic organism>

2.      Fungus is neither a plant nor an animal,

3.      It can be unicellular or multicellular,

4.      Its’ cell wall is further enhanced by chitin which doesn’t present in bacterial.

5.      It does not have chlorophyll and so is photosynthesis independent.  <Read also extra info for explanation on the consequences of photosynthesis independent>

6.      Fungi usually feed on dead organisms.

7.      Fungi can be classified based on their site of origins, structure, and type of spores produced. <Read also extra info for explanation on classification of fungi>

8.      Despite we hate fungi due to the annoying symptoms resulted from fungal infection,  they do have important contribution to human life. .  <Read also extra info for the contribution of fungi towards human life.>

9.      Squalene/ sterol found on cell membrane is known as ergosterol, wherease those found in human and animal are known as cholesterol.  <Read also extra info for explanation on the synthesis of ergosterol>

10.  Cell wall of fungus is made up of cellulose, and cell wall of prokaryotic bacterial is made up of peptidoglycan. .  <Read also extra info for explanation on  peptidoglycan>

extra info –by LAW JIA JUIN

1.      comparison between prokaryotic organism and eukaryotic organism:

5.Consequences of photosynthesis independent:

since fungus is photosynthesis independent ,it can occupy dark area and thus:L

a.       invade interior part of body

b.      grow in all direction

These make fungal infection more difficult to be treated.

8. contribution of fungi towards human life:

a. mushrooms serve as food.

b. Fungi can produce antibacterial agents eg:

i) cephalosporium gives cephalothin

 ii)penicillin notatum gives benzyl penicillin.

  iii)Fusidium coccimeum gives fusidic acid

    iv) P.Griseofulvum gives Griseofulvin

7. explanation on classification of fungi.

• Based on the site of origin

• Soil- Geophilic

• Animals- Zoophilic

• Human skin- antrhopophilic

• Based on the structure

• Unicellular- Yeasts- Candida albicans

• Multicellular- Moulds- Penicillium notatum

•Based on types of spore production

• Basidiomycetes- Basidiospores

• Ascomycetes- Ascospores

9. Explanation on the production of ergosterol:

      squalene oxide à cyclosterol

Cyclosterol à sitosterol (in plant only)

OR

Cyclosterol à ianosterol then

Ianosterolà cholesterol in animal

For fungi: Ianosterol (from cyclosterol) à ergosterol

11.explanation on  peptidoglycan:

Peptidoglycan is:

-          polymer of sugars (a glycan)

-          cross-linked by short chains of amino acids (peptide)

-          bacterial peptidoglycans contain N-acetylmuramic acid (component of murein) and N-acetylglucoasamide, bacterial murein is a unique type of peptidoglycan

See photos below:

Why is fungal infection more difficult to be treated than bacterial infection??

BCZ:

-     Fungi have rigid cell wall with chitin coated on it.

-     Cell membrane of fungi are stronger due to the present of ergosterols which contribute to the fluidity and strength of their cell membrane, thus more difficult to be penetrated by antimicrobial and tougher to be destroyed by body enzyme.

-     Mix infection (fungal infection together with bacterial infection) can be resulted, this is because fungi always invade region difficult to be penetrated by antimicrobial agents and also region which do not get enough blood supply. Lacking of blood supply mean blood cells example: white blood cells and antibiotics which fight against bacterial had failed to reach that region .Thus region of fungal infection is usually region which is prone to bacterial infection esp: anaerobic bacterial bcz less blood supply means less oxygen supply as well. Therefore usually antifungal must be used together with antibacterial for effective treatment. Treatment become even harder when the patient is immune compromised example those HIV patients or those who had taken corticosteroid for long period of time.

E.Type of fungal infection.

5 types of fungal infections:

-     Superficial infection -skin hair nail

-     Subcutaneous(upper layer of skin dermis) infection

-     Cutaneous(inner layer of skin dermis) infection

-     Systemic-fever and hypotension (caused by systemic vasodilation resulted from acute            inflammatory response, read also my previous post title: Allergic reaction and inflammatory responses by LAW JIA JUIN link: http://jiajuin0409.blogspot.com/2011/12/allergic-reaction-by-law-jia-juin.html )

-    Opportunistic infection- example HIV and TB patients.

See photos below:

F Antifungal agents/ drugs:

Classified into 6 main classes:

 1.Polyenes eg :amphotericin, nystation

·         Mechanisms of action: selectively bind to ergosterol in fungal cell membrane altering membrane fluidity and producing pores and osmotic cell death. Some people may asked since these antifungals act on sterol wouldn’t it harm human body or cell membrane as well? The answer is no, there are safe when applied to human and animals because they didn’t have much effect on human sterol (cholesterol on human cell membrane ) instead they bind specifically to fungals’ sterol which is known as ergosterol.

2.Azoles class (mostly used) eg: ketoazole, miconazole….

·         Mechanisms of action: Selectively block ergosterol synthesis (not cholesterol synthesis) by inhibiting demethylation of ianosterol. Mamalian or host P450 enzyme less affected.

3.5-flucytosine

·         Mechanisms of action: Converted by fungal cytosine deaminase into 5-fluorouracil; inhibits DNA synthesis. Mamalian cells lack cytosine deaminase so less affected by this drug.

4.Griseofulvin

·         Mechanisms of action: Inhibit fungal growth by binding to microtubules, disrupting mitotic spindles. Mamalian microtubules less affected, so does not harm human being.

5.Echinocandins eg caspofungin, micafungin, anidulofungin

·         Mechanisms of action:  Inhibits fungal Beta glucan(cell wall) synthesis, disrupting cell wall integrity. Mamalian//human host cells have no cell wall thus is not affected.

6.Allylamines eg terbinafine

•              Mechanism of action: selectively blocks ergosterol synthesis by inhibiting squalen e epoxidase(for the synthesis of ergosterol precursor, squalene oxide) . Mamalian host cells do not need this enzyme for squalene oxide production ,thus remained unaffected . < read the “Explanation on the production of ergosterol” under extra info above>

Antifungals for Superficial (Topical) mycosis:

1. Clotrimazole: usually used to treat oral, skin and vaginal fungal infection

2.Econazole: mostly applied for fungal infection on skin fold area and anus

3. Griseofulvin: used mainly for serious untreated topical infection, parenteral//injection via IV is banned since toxic. Can be fungicidal or fungistatic

4.Miconazole: effective against dermatophytes infection on skin

5.Nystatin: usually used for the treatment of tinea pedis// fungal foot infection

6.Amphotericin B: mainly used in IV treatment of fatal systemic infection, inner skin infection and throat (oropharyngeal) infection ,effective for the treatment of various fungal infections specially as

empiric therapy in immunocompromised patients.Work as both fungistatic and fungicidal at different concentrations. Although it gives broad and empiric therapy, it is only used for acute infection in hospital setting, this is due to risk and adverse effect of it, for example the problem resulted from infusion and its’nephrotoxic property.

7.Ketoconazole and others: slow acting and requires long treatment

durations. So less effective against acute infections. usually used for atopic and dermis infection

1,2,4,7 are classified under the class of azole//imidazole

So aution should be taken when these agents are

concurrently administered with:

·          Benzodiazepines, Phenytoin, Carbamazepine

·          HMG-CoA reductase inhibitors

·         Cyclosporine, Tacrolimus and Sirolimus,

·         Methylprednisolone

·          Dihydropyridine calcium channel blockers Verapamil and

·         Diltiazem

·         Sulfonylureas

·         Rifampin, Rifabutin, Vincristine, Docetaxel,

The choice of drug dependent on the type of fungus and the site of infection

Antifungals for systemic mycosis:

_ Amphotericin B: mainly for inner skin infection and throat (oropharyngeal) infection

_ Imidazoles (Fluconazole, Itraconazole, Ketoconazole, Voriconazole, Miconazole)

_ Flucytosine: for treatment of urinary bladder fungal infection

_ Griseofulvin: used mainly for serious untreated topical infection

_ Nystatin: usually used for the treatment of tinea pedis// fungal foot infection

_ Terbinafine:

The choice of drug dependent on the type of fungus and the site of infection

If the antifungal doesn’t work then a stronger or different one must be considered (also consider mix thearapy with antibacterial )because fungus can develop its’ resistance towards drug just like bacterial, for example fungus can change the structure of ergosterol produced or alter the synthetic pathway, so that antifungal can no longer target at them, fungus is as smart as bacterial, it is the race between human and  bacterial LOL.

So as a conclusion I will suggest my uncle to take a drug with the regimen of suitable antifungal and anti-inflammatory agent(treat symptoms of him) eg betamethasone + itraconazone (broad spectrum but less adverse effect than amphotericin B), and also I will advise him to take good care of personal hygience. Also I will advise him not to take antacid or H2 blocker if itraconazone is to be dispensed in oral form instead of cream form. In fact in the market there is already a cream formulation with the combination of betamethasone and antifungal(The choice of antifungal is dependent on the type of fungus and the site of infection) for treatment of topical fungal infection

G.Background 2: My uncle also told me that he was dispensed with antibiotics known as curam.

#Antibiotics are classified into 5 main types based on their target of action on bacterial call:

1.Cell wall synthesis inhibitor types (which can be further classified into Beta lactams group .Under this beta lactam group ,the antibacterial can still be classified into penicillin subgroup, cephalosporin subgroup, carbapenems subgroup. Other cell wall synthesis inhibitor include cycloserine, vamcomycin and bacitracin)

2.Protein synthesis inhibitor (not to be discussed in this article)

3.DNA inhibitor (not to be discussed in this article)

4.folic acid inhibitor  (not to be discussed in this article)

Cell membrane inhibitor (not to be discussed in this article)

Curam is actually a combination amoxycilin (a broad spectrum antibiotic)and clavulanic acid which is an beta lactamase inhibitor. Amoxycilin is relatively safe antibacterial to be used.

+Amoxycilin is situated under:

Antibiotics à Cell wall synthesis inhibitor typesà Beta lactams group(meaning to say that this antibiotic has a special beta lactam ring as its’ functional antifungal unit)àpenicilin subgroupàsecond generation with extended spectrum (gram positive and negative cocci + gram +ve gram –ve bacilli)

?Why is clavulanic acid added into this antibiotics?

This is to fight against the penicillin resisted bacterial. This resisted bacterial had developed a resistance towards beta lactam antibiotic by degrading penicilin antibiotics ,this is done by Beta lactamase enzyme produced by this evolved bacterial. So with the presence of clavulanic acid beta lactamase enzyme produced by this smart bacterial can be inactivated.

+Others ways in which bacterial can evolve and become resisted towards antibiotics (other than beta lactam types):

1With the presence of an alternative enzyme to cheat antibiotic
2Mutation in the target
3Modification of the target
4 Reduced uptake of the antibiotic 5Active efflux of the antibiotic

+Side effect of penicillin type antibiotic eg: hypersensitivity and diarhoea but not 100% will happen