Tetracyclines, Anti-fungals (Lecture 77) - PDF

 Lecture 77: [PHARM] Antimicrobial agents 4: Broad Spectrum antibiotics – Tetracycline, Chloramphenicol and Antifungal drugs Objectives: The objective of the lecture is to discuss the pharmacology of broad-spectrum antibiotics, Tetracyclines a...

 Lecture 77: [PHARM] Antimicrobial agents 4: Broad Spectrum antibiotics – Tetracycline, Chloramphenicol and Antifungal drugs Objectives: The objective of the lecture is to discuss the pharmacology of broad-spectrum antibiotics, Tetracyclines and Chloramphenicol and pharmacology of antifungal drugs. Topic Outcomes: At the end of the lecture, students should be able to: 77.1 List the broad-spectrum antibiotics. 77.2 List different tetracyclines. 77.3State the mechanism of action, therapeutic uses, adverse effects and contraindications of demeclocycline, minocycline and doxycycline. 77.4State the mechanism of action, therapeutic uses, adverse effects and contraindications of chloramphenicol. 77.5Classify antifungal drugs based on their efficacy against cutaneous fungal infections and systemic fungal infections. 77.6 State the mechanism of action, indications and adverse effects of antifungal drugs: fluconazole, ketoconazole, nystatin, griseofulvin, State the treatment of candidiasis.  ANTI MICROBIALS Tetracyclines, Chloramphenicol, Anti fungals  Antibiotics : Compounds produced by microorganisms and having inhibitory effects on other microorganisms. Tetracyclines Class of antibiotics having a nucleus of 4 cyclic rings Obtained from soil actinomycetes Broad spectrum antibiotics Mechanism of action Primarily bacteriostatic Inhibits Protein synthesis: Bind to 30S Ribosome in susceptible organisms Inhibits the binding of aminoacyl tRNA to mRNA Peptide chain fails to grow Tetracyclines Antimicrobial spectrum: – When introduced initially inhibited practically all types of pathogenic organisms except Fungi and Viruses – Hence categorised as broad spectrum antibiotic – Indiscriminate and irresponsible use has markedly reduced its spectrum due to development of resistant starins Most Gm +ve and – ve cocci, Enteric bacteria, Pseudomonas, Proteus etc are Resistant Spirochetes, Rickettsia, Chlamydia : highly sensitive Cross resistance incomplete Tetracyclines Pharmacokinetics – Orally administered – Newer tetracyclines have better oral bioavailability – Better absorbed in empty stomach : food chelates – Iron, Calcium, antacids, Metal salts, Sucralfate – Widely distributed in the body – Excreted primarily by the kidneys : Dose adjustments in Renal failure (except Doxycycline) – Secreted in breast milk : affects Neonates – Dosage : 100mg OD/BD Tetracyclines Adverse effects – Epigastric pain, Nausea, Vomiting, Diarrhea – Hepatotoxic : Fatty infiltration of liver, Jaundice – Nephrotoxic : except Doxycycline all others worsen renal failure – Fanconi syndrome : seen with use of outdated/degraded tetracyclines – Phototoxic : Sun burn, skin reactions – Teeth and Bones : Chelates with Calcium in bones and teeth. Brownish discolouration of teeth, prone to caries (mid pregnancy to 6 yrs of age) – Hyper sensitivity – Super infections : greater suppression of resident flora Pseudomonas Proteus. Less incidence with Doxycycline, Minocycline Tetracyclines Precautions: – Not to be used in Pregnancy, Lactation & children – Cautious use in pts of Renal and Hepatic insufficiency – Never use beyond expiry date Uses: have declined because of emergence of resistant strains and availability of better AMAs Chlamydia, LGV, Granuloma inguinale Atypical pneumonia,Mycoplama, CAP Cholera, Plague, Brucellosis  Demeclocycline Doxycycline Minocycline Potency Intermediate High High Intestinal absorption High High High Elimination Partial metabolism Primarily excreted in Metabolised and Slow renal excretion faeces excreted in urine Half life 12-18 18-24 18-24 hrs Dosage 300mg BD 200mg Stat 100mg OD 200mg Stat 100mg OD Alteration of intestinal Moderate Minimal Minimal flora Incidence of diarrhoea Intermediate Low Low Toxicity Phototoxic Low renal toxicity Vestibular toxicity Diabetes insipidus  Tetracyclines Tigecyclines – Newer class of synthetic tetracycline analogues – Active against most bacteria resistant to tetracyclines – Mechanism of action : similar to tetracyclines – Poorly absorbed orally : given as slow iv infusion – Eliminated mainly in bile : dose adjustments in Renal failure not needed Uses severe Community acquired pneumonia 100mg loading, 50mg 12hly for 5-14 days A/E epigastric pain, nausea, vomiting photosensitivity Not recommended for use in children and pregnancy Chloramphenicol One of the older antibiotics Initially obtained from bacteria now synthesised chemically MoA – Bacteriostatic – Binds to 50S ribosome & inhibit protein synthesis Spectrum – Similar to tetracyclines – Especially effective against Salmonella typhi Pharmacokinetics – Rapidly and completely absorbed after oral administration – Conjugated in liver with Glucuoronic acid ; caution in use in cirrhotics, Neonates, immature liver Chloramphenicol : MoA  Chloramphenicol A/E – Bone marrow suppression, aplastic anemia, agranulocytosis, Myelosuppression – Idiosyncratic reaction → aplastic anemia. Rare & Fatal Uses – Extremely limited because of mergence of resistant strains, availability of safer and better agents – Pyogenic meningitis, Enteric fever  Anti fungals Fungus: A plant-like organism that does not make chlorophyll. Mushrooms, yeasts, and molds are examples. The plural is fungi. Anti fungals Drugs used for treatment of fungal infections both superficial as well as deep (systemic) mycosis Fungal infections emerged since 1950s with use of broad spectrum antibiotics, corticosteroids, anti cancer drugs, Immunosuppressant and emergence of AIDS Breakdown of host defenses by above → fungi invading living tissues Anti fungals  Anti fungals Amphotericin B (Polyene antibiotics) : Polyene – presence of numerous double bonds – MoA: Fungicidal A macrocyclic ring with one side being lipophilic and the other hydrophilic Have high affinity for ergosterol present in fungal cell membrane On combining with ergosterol reorient themselves to form micro pores in the cell membrane. Through the pores ions , amino acids and other water soluble substances leak out → cell death Polyene antibiotics also have affinity and bind to cholesterol in host cell membrane producing a similar effect AMB is thus one of the most toxic antibiotics – Spectrum Effective against wide range of yeasts and fungi Candida, Histoplasma, Aspergillus Effective against Protozoa : Leishmania Anti fungals P’kinetics – AMB is not absorbed orally – Given IV as suspension with deoxycholates – Widely distributed in the body except CSF – 60% metabolised in liver, excreted slowly in urine – No dose adjustments needed in liver/renal disease – Administered orally for intestinal candidiasis and topically for vaginal candidiasis Administration ▪ Suspend in 10 ml water dilute with 500ml glucose solution , give iv over 4-8 hrs ▪ Watch for hypersensitivity reactions Anti fungals A/E – A highly toxic drug – Acute reaction Seen with each infusion, reduces with subsequent infusions Chills, fever, aches & pains, nausea, Vomiting, Dyspnea – Long term Nephrotoxicity – dose related Anemia – Bone marrow suppression - Reversible Anti fungals Uses – Most effective drug for all types of systemic mycosis – Gold standard of anti fungal therapy – Leishmaniasis (Kala azar) – Topically for oral, Corneal, cutaneous and vaginal candidiasis – Dose:: 0.7mg/kg as infusion over 3-4 hrs (after test dose) Total dose : 3-4 g given over 2-3 months  Liposomal AMB – Improved tolerability – Milder acute reaction – Lower nephrotoxicity Anti fungals Nystatin – Another polyene antibiotic – Obtained from S noursei – Similar to AMB in anti fungal and other properties – Has higher systemic toxicity than AMB – 5lakh U/tab, 1 lakh U/vaginal tab,1 lakh U/g oint – Used only locally for superficial candidiasis (oral & vaginal candidiasis) Anti fungals Echinocandins – Newer class of potent semi synthetic anti fungals – Much lower toxicity than AMB Caspofungin 1st and prototype member of this class MoA Inhibits synthesis of β-1 3 glucan component of fungal cell wall by inhibiting enzyme β glucan synthase → fungal cell death P’kinetics Not absorbed orally Given as freshly prepared aqueous solution as iv infusion Metabolised in liver, excreted in urine and faeces Anti fungals Uses – Deep and invasive candidiasis :70 mg loading dose IV over 1 hr, followed by 50 mg daily – Aspergillosis A/E – Acute febrile reaction – Phlebitis of injected vein – Rash, vomiting, Dyspnea, joint pains Anti fungals Griseofulvin – An antibiotic obtained from Penicillium griseofulvum – Fungistatic for most Dermatophytes – No activity against candida and deeper Mycosis MoA – Interferes with Mitosis → stunted fungal growth P’kinetics – Poor oral absorption, better with fatty meal – Keratophilic – gets deposited in keratin forming cells of skin, nails, hairs→ prevention of fungal growth – t/2 24 hrs in the body but persists for weeks in skin, nails and hairs  Anti fungals A/E – Low toxicity, generally well tolerated – Induces CYP3A4 metabolism of Warfarin – Headache, GIT disturbances, Rashes, photo allergy Uses – Used only for dermatophytosis. Fungistatic gets deposited in keratin forming cells & prevents fungal invasion of keratin – Treatment completed when infected keratin is shed off. Duration ∝ to thickness of skin. Scalp – 4 wks,nails 6-8 mths – Ineffective topically Localised Tinea – topical agents Generalised Tinea – Systemic agents Anti fungals Imidazoles and Triazoles – Presently the most extensively used anti fungal – Have Broad spectrum anti fungal activity – Dermatophytes, candidiasis MoA inhibit fungal cytochrome P450 enzyme (lanosterol 14 demethylase) →impaired ergosterol synthesis →membrane abnormalities : Fungistatic and fungicidal have lower affinity for mammalian Cytochrome enzymes low toxicity Clotrimazole – Most commonly used topical imidazole for Tinea infections (ring worms, Otomycosis, oral & vaginal candidiasis A/E local irritation, stinging No systemic toxicity on local use Anti fungals Miconazole – Highly efficacious drug for Tinea and Otomycosis – Oral and vaginal candidiasis – Has good penetration into skin, nails Oxiconazole  Anti fungals Ketoconazole – Used both topically and systemically – First orally active broad spectrum anti fungal useful for both Dermatophytes and Deep Mycosis – Oral absorption facilitated by gastric acidity – Metabolised in liver – A/E Nausea, vomiting, loss of appetite, Rashes ↓androgen production & displaces testosterone from protein binding site → gynecomastia, loss of libido, oligozoospermia, menstrual irregularities  Anti fungals Drug interactions inhibition of Cytochrome P450 levels of Phenytoin, ↑ed levels of Digoxin, warfarin etc H2 blockers, PPIs ↓ absorption Uses Dermatophytosis Seborrhea of scalp, Dandruff Anti fungals Fluconazole – Water soluble triazole with wide spectrum of anti fungal activity – P’kinetics Has good oral bioavailability Bioavailability not affected by food or gastric pH – A/E Nausea, vomiting , abdominal pain, rashes, headache Lesser degree of anti androgenic activity, Cyt enzyme inhibition – Uses Fungicidal. Given orally as well as IV Oral candidiasis, Tinea infections :100mg /day X 2 weeks Disseminated candidiasis, fungal infection in AIDS pts 200-400mg /day X 4-12 weeks Anti fungals Itraconazole – Orally active triazole anti fungal having broader spectrum of activity than other azoles – P’kinetics Variable oral absorption , ↓ by food & gastric acid Widely distributed in body including skin and nails Poor penetration in CSF No steroid hormone synthesis inhibitor – A/E Well tolerated at doses ˂ 200 mg/day Dizziness, pruritus, headache, Hypokalemia Hepatotoxic – Uses Systemic mycosis, Vaginal candidiasis Dermatophytes : 100 – 200 mg/day for 7 – 10 days  Anti fungals Voriconazole – 2nd generation broad spectrum azoles – Used in the treatment of difficult to treat fungal infections : invasive Aspergillosis, Candida, Histoplasmosis , Blastomycosis – Well absorbed orally Anti fungals Allylamines – Terbinafine – Orally and topically active drug against Dermatophytes & Candida – MoA Fungicidal Non competitive inhibitor of Squalene epoxidase →accumulation of squalene within fungal cells →fungal cell death – P’kinetics Well absorbed orally Undergoes 1st pass metabolism F ˂ 50% Widely distributed, high affinity for keratin – A/E Well tolerated Gastric upset, headache, rashes, Hepatic dysfunction  Anti fungals – Uses 1% cream for Tinea infections : 2-4 wks Orally for Onchomycosis : 3-6 mths Tolnaftate – Poor penetration of skin so not preferred for nails, soles infection – Topically used anti fungal for dermatophytosis, – Tinea cruris & corporis Ciclopirox oleamine – Newer drug for treatment ofTinea, Pitryiasis versicolor – Has good keratin penetration but poor systemic absorption 1% cream Uses: Onchomycosis, Vaginal candidiasis  Candidiasis is a fungal infection caused by an overgrowth of a type of yeast that lives on the body (Candida albicans). A candidiasis infection often appears on the skin, vagina or mouth, where Candida naturally lives in small amounts. Healthy bacteria on the body prevent yeast overgrowth. The scale stays balanced until disruption occurs from stress, a poor dietlly lives in your body, there are different types of candidiasis based on the location of the infection. Types of candidiasis include: Vaginal candidiasis (vaginitis): Cutaneous candidiasis: An infection of the skin in folds of skin, like in underarms, under breasts and buttocks (diaper rash) or groin. Oral candidiasis (thrush): An infection that causes white sores in mouth, throat, esophagus, or tongue. Candida granuloma: A severe, chronic infection that targets skin, scalp, mouth or fingernails. Invasive candidiasis (systemic candidiasis): because of a weakened immune system or an uncontrolled medical condition.