Synthetic organic antimicrobials

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Chapter 42 Tetracyclines and
Chloramphenicol
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Tetracyclines

• Natural
• Tetracycline, oxytetracycline,
  chlortetracycline
• Semi-synthesized
• Doxycycline and minocycline

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Tetracyclines

• Antimicrobial activity
• Broad-spectrum bacteriostatic antibiotics
• Many gram-positive and gram-negative bacteria
  including anaerobes
• Rickettsiae, chlamydiae and mycoplasm
• Some protozoa amebas

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Tetracyclines

• Mechanism of action
• Tetracyclines bind reversibly to the 30s
  subunit of bacterial ribosome and block the
  binding of aminoactyl-tRNA to the acceptor site,
  prevent the elongation of peptide.

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Tetracyclines

• Resistance
• Production of an efflux pump
• Ribosome protection due to production of proteins
  that interfere with tetracyclines binding to the
  ribosome
• Production of enzyme

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Tetracycline

• Pharmacokinetics
• Absorption affected by food ,divalent
  cations(Ca2, Mg2 , Fe2 ), dairy products and
  antiacid
• Distribution distribute widely to tissues and
  body fluids, bind to and damage growing bone and
  teeth as a result of chelation with calcium
• Cross plancental barrier and excrete in milk

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Tetracyclines

• Clinical uses
• Rickettsiae infections first choice
• Chlamydiae pneumoniae
• Mycoplasma infection
• Relapsing fever the most effective
• Various gram-positive and negative infections
• Gastric ulcer and duodenal ulcer caused by
  Helicobacter pylori in combination regimens

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Tetracycline

• Adverse reactions
• Gastrointestinal adverse effects
• Superinfection
• Pseudomembranous enterocolitis caused by
  clostridium difficile
• Candida albicans infection
• Effects on bony structure and teeth
• Teeth fluorescence, discoloration and enamel
  dysplasia
• Bone deformity or growth inhibition
• Liver and kidney toxicity, photosensitization

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Synthesized tetracyclines

• Doxycycline and minocycline
• Almost completely absorbed
• Long-acting t 1/2 gt14h
• Higher activity than tetracycline
• Effective against tetracycline-resistant bacteria
• Low toxicity
• Minocycline the strongest activity/ vestibular
  disturbance

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Chloramphenicol
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Antimicrobial activity

• Broad-spectrum bacteriostatic antibiotics
• Both gram-positive and gram-negative aerobic and
  anaerobic organisms
• Rickettsiae, spirochetes, mycoplasm

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Mechanism of action

• Chloramphenicol is a inhibitor of
  microbial protein synthesis. It binds reversibly
  to the 50s subunit of the ribosome and inhibits
  the peptidyl transferase step of protein synthesis

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Pharmacokinetics

• Absorption po
• High concentration in CSF
• Metabolized in liver

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Clinical uses

• Bacterial menigitis caused by penicillin-resistant
  bacteria or penicillin-allergic patients
• Typhoid and paratyphoid fever first choice
• Serious rickettsial infections
• Topical use for treatment of eye infections

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Adverse reactions

• Bone marrow disturbances
• Reversible suppression of RBC production
• Ireversible aplastic anemia
• Gray baby syndrome
• dose gt50mg/kg/d
• Gastrointestinal reactions

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Chapter 43 Synthetic organic antimicrobials
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Synthetic organic antimicrobials

• Quinolones
• Sulfonamides
• Trimethoprim(TMP)
• Nitrofurans
• Metronidazole

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Quinolones

• Brief introduction
• Antibacterial activity
• Mechanism of action
• Clinical uses
• Adverse reactions

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Brief introduction of quinolones

• Four generations
• First generation1962 Lesher nalidixic acid
• Second generation 1973 pipemidic acid
• Third generation 1980s fluoroquinolones
• Fourth generation late 1990s
  moxifloxacin(????), gatifloxacin(????)

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Nalidixic acidfirst generation

• Narrow antibacterial spectrumG-
• Poorly absorbed
• High adverse reactions

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Pipemidic acid--second generation

• Higher activity than nalidixic acid
• High concentration in urine
• Less toxicity than nalidixic acid
• Mainly used in gastrointestinal and urinary tract
  infection

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Fluoroquinolonesthird generation

• Norfloxacin ????
• Ciprofloxacin????
• Ofloxacin ????
• Levoofloxacin?????
• Lomefloxacin ????
• Fleroxacin ????
• Sparfloxacin ????

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Fluoroquinolones

• Antibacterial activity broad spectrum
• Excellent activity against gram-negative aerobic
  bacteria include enterobacteriaceae, neisseria,
  pseudomonas, haemophilus(?????) and
  campylobacter(?????) etc
• Good activity against gram-positive aerobic
  bacteria eg pneumoniae and staphylococci
• Mycoplasmas, chlamydiae, mycobaterium
  tuberculosis, legionella and anaerobes

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Quinolones

• Mechanism of action
• To G- DNA gyrase A2B2
• To G Topo ? C2E2
• Resistance
• Mutation of target gyrA or parC
• Lack of OmpF on membrane
• Active efflux pump

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Fluoroquinolones

• Pharmacokinetics
• Absorbed rapidly and completely
• Widely distributed
• Long T ½
• Low adverse reaction
• No cross-resistance with other drugs

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Fluoroquinolones

• Clinical uses
• Urinary and genital tract infections
• Respiratory tract infection Legionella ,
  chlamydia and mycoplasma pneumonia
• Bacterial diarrhea caused by shigella, salmonella
  or campylobacter
• Infections of soft-tissues, bones, joint
• Tuberculosis Ofloxacin, Sparfloxacin

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Fluoroquinolones

• Adverse reactions
• Gastrointestinal reaction nausea, vomiting and
  diarrhea
• CNS headache, dizziness, insomnia and anxiety,
  seizure
• Allergic effect skin rash, photosensitivity
• Damage growing cartilage and cause arthropathy

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Contradications

• Pregnancy
• Children
• CNS disorder
• History of epilepsy
• Allergic

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Commonly used Quinolones
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• Nalidixic acid and pipemidic acid
• Used only in urinary tract infection
• Norfloxacin
• The least active in fluoroquinolones, F low
• No effects on mycoplasmas, chlamydiae,
  mycobaterium tuberculosis, legionella
• Urinary tract and intestinal tract infections
• Ciprofloxacin(???)
• The most active agent in fluoroquinolones against
  gram-negatives, particularly P. aeruginosa in
  vitro
• No effects on anaerobes

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• Ofloxacin(????)
• Improved quality in pharmacokinetics F 89
• Effective on mycobateria, chlamydiae and some
  anaerobes
• Effective on resistant bacteria
• Second line agent for tuberculosis
• Levo-ofloxacin(????,???)
• F 100
• Superior activity against gram-positive organisms
• Effective on mycoplasma, legionella, chlamydia
  and anaerobes
• Lowest toxicity among fluoroquinolones

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• Lomefloxacin
• F 98 t ½ 7h
• To G and G- Similar to ofloxacin
• To anaerobes lt ofloxacin
• Photosensitivity C8-F
• Fleroxacin
• F 100, t ½gt10h
• Higher activity than ciprofloxacin and ofloxacin
• (in vivo)

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• Sparfloxacin
• Long-acting t ½gt16h
• Improved activity against G bacteria, anaerobes,
  mycobateria, mycoplasmas, chlamydiae
• Second line agent for tuberculosis
• Moxifloxacin fourth generation
• F 90 t ½ 1215h
• High activity on most G ,G-, anaerobes,
  mycobateria, mycoplasmas, chlamydiae
• Low toxicity

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Sulfonamides
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Sulfonamides

• Classification
• Used in systemic infections
• Short-acting SIZ
• Medium-acting SD, SMZ
• Long-acting SMD
• Used in intestinal infections sulfasalazine
• Topic sulfonamides SD-Ag, SA-Na, SML

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Sulfonamides

• Antimicrobial activity
• Broad-spectrum bacteriostatic agents
• Both G and G- , chlamydiae trachomatis
  
• mycoplasm and some protozoa
• Mechanism of action
• Inhibit dihydropteroate synthetaseand block
  bacteria folic acid synthesis

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Sulfonamides

• Pharmacokinetics
• Metabolism liver
• Excretion kidney pH

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Sulfonamides

• Adverse effects
• Urinary tract disturbance crystalluria,
  hematuria, obstruction
• Allergic reactions fever, skin rashes,
  exfoliative dermatitis, photosensitivity
• Hematopoietic disturbances
• Granulocytopenia, thrombocytopenia
• Hemolytic reactions
• lack of glucose-6-phosphate dehydrogenase
• CNS reaction headache, vertigo

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Sulfonamides

• Clinical uses
• Urinary tract infection SIZ, SMZ
• Meningococcal meningitis SD first choice
• Ulcerative colitis sulfasalazine(SASP)
• Bacterial dysentery SMZ
• Topical use for trachoma and conjunctivitis
  SA-Na
• Prevent infections of burn wounds SD-Ag, SML

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Trimethoprim (TMP)

• Inhibit bacterial dihydrofolate reductase
• Used in combination with sulfonamides synergism
• SMZTMP (SMZco,?????)
• Toxicity teratogenesis

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Nitrofurans

• Nitrofurantoin
• Low blood concentration
• Urinary tract infection
• Furazolidone
• Poorly absorbed
• Gastrointestinal tract infection
• H.p infection

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Metronidazole

• Antimicrobial activity and clinical uses
• Extraluminal amebiasis drug of choice
• Infections caused by anaerobes
• Giardiasis
• Trichomoniasis
• H.p infection

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Metronidazole

• Adverse reactions
• Gastrointestinal irritation metallic taste in
  mouth, nausea, dry mouth
• Disulfiram-like effect
• CNS vertigo, parensthesias, ataxia and seizures
• Mutagenic and carcinogenic

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Tinidazole (???)

• Higher activity 2
• Good pharmacokinetics
• Long t 1/2
• Penetrate tissue well
• High concentration in CSF 88
• Less toxicity

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THE END
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