Transcript Synthetic organic antimicrobials

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
bacteria including anaerobes
• Rickettsiae, chlamydiae and mycoplasm
• Some protozoa: amebas
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.
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
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
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
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
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
disturbance
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 penicillinresistant bacteria or penicillin-allergic
patients
 Typhoid and paratyphoid fever :first
choice
 Serious rickettsial infections
 Topical 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
 Quinolones
 Sulfonamides
 Trimethoprim（TMP）
 Nitrofurans
 Metronidazole
Quinolones
 Brief
introduction
 Antibacterial activity
 Mechanism of action
 Clinical uses
 Adverse 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
tract infection
Fluoroquinolones—third generation
—— 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
 Norfloxacin
Fluoroquinolones
Antibacterial
activity： broad spectrum
Excellent activity against gram-negative aerobic
bacteria 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
To G+: Topo Ⅳ
A2B2
C2E2
 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 ,
chlamydia and mycoplasma pneumonia
Bacterial diarrhea caused by shigella,
salmonella 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
anxiety, seizure
Allergic effect: skin rash, photosensitivity
Damage growing cartilage and cause
arthropathy
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,
mycobaterium tuberculosis, legionella
Urinary tract and intestinal tract infections
 Ciprofloxacin(悉复欢)
The most active agent in fluoroquinolones against
gram-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
anaerobes
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
and 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
 F 90%
fourth generation
t ½ 12~15h
High activity on most G+ ,G-, anaerobes,
mycobateria, mycoplasmas, chlamydiae
Low toxicity
Sulfonamides
Domagk
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
Sulfonamides
 Antimicrobial
activity
Broad-spectrum bacteriostatic agents
Both G+ and G- , chlamydiae trachomatis
mycoplasm and some protozoa
 Mechanism
of action
Inhibit dihydropteroate synthetase
and 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 disturbances
Granulocytopenia, thrombocytopenia
Hemolytic 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 reductase
 Used in combination with sulfonamides:
synergism
 SMZ+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
in mouth, nausea, dry mouth
Disulfiram-like effect
CNS: vertigo, parensthesias, ataxia and
seizures
Mutagenic and carcinogenic
Tinidazole (替硝唑）
 Higher
activity 2
 Good pharmacokinetics
 Long t
1/2
 Penetrate tissue well
 High concentration in CSF
 Less
toxicity
88%