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ANTIBIOTICSIntroduction To Tetracyclines And QuinolonesPrepared By:Tareq Tareq,B.Pharm Student,International Islamic University Chittagong,Bangladesh.

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TetracyclinesTetracyclines are a group of broad-spectrum antibioticsThey are natural product derived from Streptomyces sp

Tetracyclines are so named for their four (tetra) hydrocarbon rings

TetracyclinesThe general usefulness of Tetracyclines has been reduced with the onset of antibiotic resistance. Despite this, they remain the treatment of choice for some specific indications

General Consideration- Source: Streptomyces grasius, a soil organism- Spectrum: Broad spectrum of activity i.e., active against both gm(+) and gm(-) bacteria- Mode of action: Bacteriostatic in nature- Mechanism of ACTION: Protein synthesis inhibition

History The development of the tetracycline antibiotics was the result of a systemic screening of soil specimens collected from many parts of the world for antibiotic-producing microorganisms. The first of these compounds chlortetracycline was introduced in 1948 followed by oxytetracycline and tetracycline in 1950 and 1952 respectively.

TypesTetracyclines are of three types:

1. Natural Tetracycline: (Short acting) - Chlortetracycline (S.aureofaciens ) - Oxytetracycline (S. rimosus ) - Demeclocycline (S. aureofaciens )

Types2. Semisynthetic Tetracycline: (long acting) -Doxycyclicline - Methecycline - Minocycline

3. Both natural and semisynthetic: -Tetracycline : Natural from S. grasius Semisynthetic from Chlortetracycline

Mechanism of ActionTetracycline

Enters into bacteria by -passive diffusion -Active transport

Binds reversibly to receptor on the 30s ribosomal subunit

Block the binding of charged aminoacyl tRNA to the A site of the ribosome mRNA complex

(-) addition of aminoacid in growing peptide chain

(-) Protein synthesis

(-) Bacterial growth & multiplicationNote: At high conc. they can inhibit protein synthesis of mammal cell

Mechanism of Tetracycline resistance >>The drug is not actively transported into the cell>>The drug leaves the cell so rapidly that the required conc. Of the drug is not maintained>>Enzymatic inactivation of tetracycline>>Production of protein that interferes binding of tetracycline to ribosome

Therapeutic usesDrug of first choice Rickettsial infection -Rocky mountain spotted fever -Typhus -Rickettsialpox Mycoplasma infection -Mycoplasma pneumonia Borrelia infection -Lyme disease -Relapsing fever Vibrio infection -Cholera Plague, brucellois ( with aminoglycoside)

Therapeutic usesDrug of second choice Diarrhoea Dysentery Mixed bacterial infection e.g. respiratory tract infection Acne SIADH (Syndrome of inappropriate ADH secretion) Leptospiral infection Tularemia (An acute plague like infectious disease Caused by Francisella tularensis transmitted to the human by the bite of an infected tick or other blood sucking insect Weils disease

Adverse effectA) Organ/ system toxicity GIT -Nausea -Vomiting -Diarrhoea -Alteration of intestinal flora Hepatotoxicity Nephrotoxicity (due to inhibition of protein synthesis) -Renal tubular acidosis -Nephrogenic diabetes insipidus -Fanconis syndrome Bony stucture and teeth: -Discoloration and hypoplasia of teeth Vestibular toxicity: -Dizziness -Vertigo

Adverse effectB) Super infection: -Candida or resistant staphylococci

C) Hypersensitivity: -Urticaria -Anaphylaxix -Angioedema

ContraindicationPregnancy and lactationYoung children ( up to 8 years)Renal failureHistory of hypersensitivity

Oxytetracycline Indications: -treatment of Spirochaetal infection. -treatment of Non-Specific-Urethritis. -treatment of Clostridial wound infection and Anthrax. Contraindication: -Renal impairment -Pregnancy & breast feeding -SLE (Systemic lupus eryyhematosus)Side effects: -Local irritation after intramuscular injection. -Gastrointestinal:-anorexia, nausea, vomiting. -Renal toxicity. -Hypersensitivity reactions:Urticaria. -Blood:Hemolytic anemia, thrombocytopenia, neutropenia

OxytetracyclineDose: 250-500 mg every 6 hoursMarket preparations: ( Bangladesh) -Renamycin (Renata) -Oxecylin (ACME) -Oxycap (Globe Pharma)

DoxycyclineIndications: -Treatment of chronic adult periodontitis. -Chronic prostatitis -BrucellosisContraindication: -Renal impairment -Pregnancy & breast feeding -SLE (Systemic lupus eryyhematosus)Side effects: -Watery diarrhea -Bloody stools -photosensitivity, rash

DoxycyclineDose: -By mouth 200 mg on first day, then 100 mg daily -In severe infections 200 mg daily for 4 days

Market preparations: -Doxin (Opsoni) -Doxy-A (ACME) -Servidoxyne (Novartis)

TetracyclineIndications: -Tetracycline's primary use is for the treatment of acne vulgaris and rosacea. -It is also used to treat a very wide range of infections.Contraindication: -Renal impairment -Pregnancy & breast feeding -SLE (Systemic lupus eryyhematosus)Side effects: -Superinfection -Enamel dysplasia -Impairment in bone growth

TetracyclineDose: -By mouth 250 mg every 6 hours -Increased in severe infections to 500 mg every 6-8 hours

Market preparations: -Jmycin (Jayson) -Tetracycline (Opsonin) -Tetracyn (Renata) -Tetrax (Square)

QuinolonesThe quinolones are family of synthetic broad spectrum antibacterial drugsQuinolones exert their antibacterial effect by preventing bacterial DNA from unwinding and duplicatingThe majority of quinolones in clinical use belong to the subset fluroquinolones

HistoryThe first generation of quinolones began with the introduction of nalidixic acid in 1962 for treatment of urinary tract infections in humans. Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis.

TypesA) First generation:Non flurinated quinolone Narrow spectrum -Nalidixic acid

B) Second generation: Flurinated quinolones, 6o times more active then nalidixic acidBroad spectrumNot effective against anaerobes and community acquired pneumonia caused by Streptococcus pneumoniae -Ciprofloxacin -Enoxacin -Lomefloxacin -Acrosoxzacin -Norfloxacin -Ofloxacin

TypesC) Third generation:Broad spectrumEffective against anaerobes and community acquired pneumonia caused by Streptococcus pneumoniae -Sparfloxacin -Levofloxacin D) Fourth generation:More effective against anaerobes and community acquired pneumonia caused by Streptococcus pneumoniae -Moxifloxacin -Trovafloxacin

Mechanism of ActionMechanism of action: -Inhibit bacterial DNA synthesis by inhibiting DNA gyrase and topo-isomerase IV resulting to rapid cell death -Post antibiotic effect: lasts 1 to 2 hours, increases with increasing concentration

Mechanism of ActionQuinolone

Enter into cell via passive diffusion

(-) Rejoining of DNA

(-) Supercoiling of DNA

Cell death

Note: Quinolone (-) human DNA gyrase only at much higher conc. i.e., 100-1000 gm/ml

Mechanism of Quinolone resistanceChromosomal: -Alter target enzymes: DNA gyrase and topoisomerase IV -Decreased drug penetration: Pseudomonas, E. coliPlasmid: seen in some K. pneumoniae and E. coliMutations in both target enzymes are needed to produce significant resistance

Therapeutic usesUrinary tract infectionsGastrointestinal infections -Enteric fever -Bacillary dysentery -SepticaemiaRespiratory tract infections (but not in pneumococcal pneumoniaGynecological infectionIntra-abdominal infectionSevere systemic infection

Adverse effects -Tendon inflammation -Arthralgia -Myalgia -Hypersensitivity reactions (sometimes involving blood cells -Photosensitivity -Nausea, Vomiting

Contraindication -Epilepsy -myasthenia gravis -Pregnant and lactating women -Children

Nalidixic acidIndications: -In complicated UTIContraindication: -Hypersensitivity to drug -Porphyria -Liver disease -Renal impairmentSide effects: -Psychosis -Cranial nerve palsy -Metabolic acidosis

Nalidixic acidDose: By mouth 1g every 6hours for 7 days

Market preparations: -Naligram (ACME) -Nebactil (Beximco) -Utirex (Opsonin)

CiprofloxacinIndications: - Nosocomial pneumonia - Intra-abdominal infections -Uncomplicated/complicated UTI -Anthrax exposure and prophylaxisContraindications: -Pregnant and lactating women -myasthenia gravis -HypersensitivitySide effects: -CNS toxicity -GIT upset -Hypersensitivity

CiprofloxacinDose By mouth, -In RTI 250-500 mg every 12 hours -In pseudomonal lower RTI 750 mg twice daily -In UTI 250-500 mg twice daily

Market preparations: -Beuflox (Incepta) -Cipro-A (ACME) -Flontin (Renata) -Neofloxin XR (Beximco)

LomefloxacinIndications: -Treatment of bronchitis due to H. inflenzae -UTIContraindications: -Pregnant and lactating women -myasthenia gravis -HypersensitivitySide effects: -Phototoxicity -CNS toxicity -GIT upset -Hypersensitivity

LomefloxacinDose: 400 mg once daily

Market preparations: -Lomeflox (Aristopharma) -Mexio (Square) -Namicin (Nipa)

OfloxacinIndications: -UTI -Lower RTI -Gonorrhea -CervicitisContraindications: -Hepatic and renal impairment -History of psychiatric illnessSide effects: -Hypersensitivity reactions (sometimes involving blood cells) -Photosensitivity -Nausea, Vomiting

OfloxacinDose:By mouth, -UTI: 200-400 mg daily in the morning. Increased up to 400 mg twice daily for upper UTI -Chronic prostatitis 200 mg twice daily for 28 days -Lower RTI 400 mg daily in the morning

Market preparations: -Oflacin (Drug Intl.) -Rutix (Square)

Levofloxacin Indications: -Chronic bronchitis and CAP - Nosocomial pneumonia -SSTIs -Intra-abdominal infectionsContraindications: -Renal impairment -Pregnant and lactating women -Children Side effects: -Asthenia -Rarely tremor -Anxiety -Tachycardia -Hypotension -Hypoglycemia

Levofloxacin Dose: Oral, -Acute sinusitis: 500mg daily for 10-14 days -Exacerbation of chronic bronchitis: 250-500 mg daily for 7-10 days -Community acquired pneumonia: 500 mg once or twice daily for 7-14 days

Market preparations: -Evo (Beximco) -Exolev (Novartis) -Levoking (Renata) -Trevox (Square)

MoxifloxacinIndications: -Chronic bronchitis -Bacterial conjuctivitis -Sinusitis Contraindications: -Should be avoided in patients with existing QT prolongationside effects: -CNS toxicity -GIT upset -Hypersensitivity

MoxifloxacinDose: Adult dose is 400 mg daily

Market preparations: -Maximox (Orion) -Odycin (Beximco) -Optimox (aristopharma)

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