chapter 42 tetracyclines and chloramphenicol
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Chapter 42 Tetracyclines and Chloramphenicol. Tetracyclines. Natural: Tetracycline, oxytetracycline, chlortetracycline Semi-synthesized Doxycycline and minocycline. Tetracyclines. Antimicrobial activity Broad-spectrum bacteriostatic antibiotics - PowerPoint PPT PresentationTRANSCRIPT
Chapter 42
Tetracyclines and Chloramphenicol
Tetracyclines
Natural:
Tetracycline, oxytetracycline, chlortetracycline
Semi-synthesized
Doxycycline and minocycline
Tetracyclines
• Antimicrobial activity• Broad-spectrum bacteriostatic antibiotics• Many gram-positive and gram-negative ba
cteria including anaerobes• Rickettsiae, chlamydiae and mycoplasm• Some protozoa: amebas
Tetracyclines
Mechanism of action Tetracyclines bind reversibly to the 30s s
ubunit of bacterial ribosome and block the binding of aminoactyl-tRNA to the acceptor site, prevent the elongation of peptide.
Tetracyclines
Resistance Production of an efflux pump Ribosome protection due to produc
tion of proteins that interfere with tetracyclines binding to the ribosome
Production of enzyme
Tetracycline
Pharmacokinetics Absorption: affected by food ,divalent cation
s ( 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
Tetracyclines
• Clinical uses Rickettsiae infections : first choiceChlamydiae pneumoniae Mycoplasma infectionRelapsing fever: the most effectiveVarious gram-positive and negative infectionsGastric ulcer and duodenal ulcer caused by He
licobacter pylori in combination regimens
Tetracycline Adverse reactions
Gastrointestinal adverse effects Superinfection
Pseudomembranous enterocolitis caused by clostridium difficile
Candida albicans infection
Effects on bony structure and teethTeeth: fluorescence, discoloration and enamel dysplasiaBone: deformity or growth inhibition
Liver and kidney toxicity, photosensitization
Synthesized tetracyclines
Doxycycline and minocycline Almost completely absorbed Long-acting: t 1/2 >14h
Higher activity than tetracycline Effective against tetracycline-resistant bacteria Low toxicity Minocycline: the strongest activity/ vestibular distu
rbance
Chloramphenicol
Antimicrobial activity
Broad-spectrum bacteriostatic antibiotics
Both gram-positive and gram-negative aerobic and anaerobic organisms
Rickettsiae, spirochetes, mycoplasm
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
Pharmacokinetics
Absorption : po High concentration in CSF Metabolized in liver
Clinical uses
Bacterial menigitis caused by penicillin-resistant bacteria or penicillin-allergic patients
Typhoid and paratyphoid fever :first choice
Serious rickettsial infectionsTopical use for treatment of eye infections
Adverse reactions
Bone marrow disturbances Reversible suppression of RBC production Ireversible aplastic anemia
Gray baby syndrome dose >50mg/kg/d
Gastrointestinal reactions
Chapter 43
Synthetic organic antimicrobials
Synthetic organic antimicrobials
QuinolonesSulfonamidesTrimethoprim ( TMP )Nitrofurans Metronidazole
Quinolones
Brief introductionAntibacterial activity Mechanism of actionClinical usesAdverse reactions
Brief introduction of quinolones
Four generations First generation:1962 Lesher nalidixic acid
Second generation: 1973 pipemidic acid Third generation: 1980’s fluoroquinolones Fourth generation: late 1990’s moxifloxacin
(莫西沙星) , gatifloxacin( 加替沙星 )
Nalidixic acid—first generation
Narrow antibacterial spectrum:G- Poorly absorbed High adverse reactions
Pipemidic acid--second generation
Higher activity than nalidixic acid High concentration in urine Less toxicity than nalidixic acid Mainly used in gastrointestinal and urinary tr
act infection
Fluoroquinolones—third generation
Norfloxacin —— 诺氟沙星 Ciprofloxacin—— 环丙沙星 Ofloxacin —— 氧氟沙星 Levoofloxacin—— 左氧氟沙星 Lomefloxacin —— 洛美沙星 Fleroxacin —— 氟罗沙星 Sparfloxacin —— 司帕沙星
Fluoroquinolones
Antibacterial activity : broad spectrum Excellent activity against gram-negative aerobic ba
cteria include enterobacteriaceae, neisseria, pseudomonas, haemophilus (嗜血杆菌属) and campylobacter (弯曲杆菌属) etc
Good activity against gram-positive aerobic bacteria : eg pneumoniae and staphylococci
Mycoplasmas, chlamydiae, mycobaterium tuberculosis, legionella and anaerobes
Quinolones
Mechanism of action To G-: DNA gyrase A2B2
To G+: Topo CⅣ 2E2
Resistance Mutation of target : gyrA or parC Lack of OmpF on membrane Active efflux pump
Fluoroquinolones
Pharmacokinetics Absorbed rapidly and completely Widely distributed Long T ½ Low adverse reaction No cross-resistance with other drugs
Fluoroquinolones Clinical uses
Urinary and genital tract infections Respiratory tract infection: Legionella , chla
mydia and mycoplasma pneumonia Bacterial diarrhea caused by shigella, salm
onella or campylobacter Infections of soft-tissues, bones, joint Tuberculosis : Ofloxacin, Sparfloxacin
Fluoroquinolones
Adverse reactions Gastrointestinal reaction: nausea, vomiting
and diarrhea CNS: headache, dizziness, insomnia and anx
iety, seizure Allergic effect: skin rash, photosensitivity Damage growing cartilage and cause arthro
pathy
Contradications
Pregnancy Children CNS disorder History of epilepsy Allergic
Commonly used Quinolones
Nalidixic acid and pipemidic acid Used only in urinary tract infection
Norfloxacin The least active in fluoroquinolones, F low No effects on mycoplasmas, chlamydiae, mycobater
ium tuberculosis, legionella Urinary tract and intestinal tract infections
Ciprofloxacin( 悉复欢 ) The most active agent in fluoroquinolones against g
ram-negatives, particularly P. aeruginosa in vitro No effects on anaerobes
Ofloxacin( 泰利必妥) Improved quality in pharmacokinetics F 89% Effective on mycobateria, chlamydiae and some a
naerobes Effective on resistant bacteria Second line agent for tuberculosis
Levo-ofloxacin (可乐必妥 , 来立信) F 100% Superior activity against gram-positive organisms Effective on mycoplasma, legionella, chlamydia a
nd anaerobes Lowest toxicity among fluoroquinolones
Lomefloxacin: F 98% t ½= 7h
To G+ and G-: Similar to ofloxacin To anaerobes: < ofloxacin Photosensitivity C8-F
Fleroxacin F 100%, t ½>10h
Higher activity than ciprofloxacin and ofloxacin
(in vivo)
Sparfloxacin Long-acting t ½>16h Improved activity against G+ bacteria, anaerobes,
mycobateria, mycoplasmas, chlamydiae Second line agent for tuberculosis
Moxifloxacin fourth generation F 90% t ½ 12~15h High activity on most G+ ,G-, anaerobes, mycobate
ria, mycoplasmas, chlamydiae Low toxicity
Sulfonamides
Domagk
Sulfonamides
Classification Used in systemic infections
Short-acting: SIZMedium-acting: SD, SMZLong-acting: SMD
Used in intestinal infections: sulfasalazine Topic sulfonamides: SD-Ag, SA-Na, SML
Sulfonamides
Antimicrobial activity Broad-spectrum bacteriostatic agents Both G+ and G- , chlamydiae trachomatis
mycoplasm and some protozoaMechanism of action
Inhibit dihydropteroate synthetaseand block bacteria folic acid synthesis
Sulfonamides
Pharmacokinetics Metabolism: liver Excretion : kidney pH
Sulfonamides Adverse effects
Urinary tract disturbance: crystalluria, hematuria, obstruction
Allergic reactions: fever, skin rashes, exfoliative dermatitis, photosensitivity
Hematopoietic disturbancesGranulocytopenia, thrombocytopeniaHemolytic reactions lack of glucose-6-phosphate dehydrogenase
CNS reaction: headache, vertigo
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
Trimethoprim ( TMP )
Inhibit bacterial dihydrofolate reductaseUsed in combination with sulfonamides:
synergismSMZ+TMP (SMZco, 复方新诺明 )
Toxicity: teratogenesis
Nitrofurans Nitrofurantoin
Low blood concentration Urinary tract infection
Furazolidone Poorly absorbed Gastrointestinal tract infection H.p infection
Metronidazole
Antimicrobial activity and clinical uses Extraluminal amebiasis: drug of choice Infections caused by anaerobes Giardiasis Trichomoniasis H.p infection
Metronidazole
Adverse reactions Gastrointestinal irritation: metallic taste i
n mouth, nausea, dry mouth Disulfiram-like effect CNS: vertigo, parensthesias, ataxia and se
izures Mutagenic and carcinogenic
Tinidazole ( 替硝唑)
Higher activity 2 Good pharmacokinetics
Long t 1/2
Penetrate tissue well High concentration in CSF 88%
Less toxicity