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

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