Introduction to antimicrobial drugs
Section I. Basic concepts of antimicrobial drugs
1, antibacterial drugs: refers to drugs that have an inhibitory or killing effect on pathogenic bacteria.
2, antibacterial spectrum: the scope of antibacterial drugs to inhibit or kill pathogenic microorganisms.
(1) Narrow spectrum: refers to only a single species or a single genus of bacteria have antibacterial effect.
(2) broad spectrum: not only for bacteria, but also for chlamydia, mycoplasma, rickettsia, spirochetes and protozoa. Xu Xinbao, Department of Hepatobiliary Surgery, Air Force General Hospital
3, antibacterial activity: refers to the ability of antibacterial drugs to inhibit or kill bacteria.
4.Minimum Inhibitory Concentration (MIC): the lowest concentration that inhibits the growth of bacteria in the culture medium.
Minimum bactericidal concentration (MBC): the lowest concentration that kills bacteria in the culture medium.
5, bacteriophage: only inhibit the growth of bacteria, reproduction, but can not kill the drug.
Bactericidal drugs: drugs that can both inhibit the growth and reproduction of bacteria and kill them.
6.Chemotherapy index (CI).
(1) concept: the ratio of the animal half lethal dose (LD50) and the half effective dose (ED50) for the treatment of infected animals.
CI=LD50/ED50 or CI=LD5/ED95
(2) Significance: It is an index to evaluate the safety of chemotherapeutic drugs; the greater the CI, the higher the efficacy, the lower the toxicity, the safer the use of drugs. However, CI cannot be used as the only basis for safety evaluation.
7, antibiotic after-effect (PAE): antibiotics in the withdrawal of its concentration is lower than the minimum inhibitory concentration, the bacteria are still subject to lasting inhibition effect.
Section II mechanism of action of antibacterial drugs
I. Inhibition of bacterial cell wall synthesis.
1, the bacterial cell wall is mainly composed of peptidoglycan (mucopolysaccharide), G + bacterial mucopolysaccharide content, G – bacterial mucopolysaccharide content less.
2, drugs: b-lactams, vancomycin, bacillus peptides
Second, increase the permeability of the cytoplasmic membrane.
1, the cytoplasmic membrane is composed of phospholipid bilayer and proteins embedded in it.
2, fungal plasma membrane contains ergosterol, mammalian plasma membrane contains cholesterol, bacterial plasma membrane is neither cholesterol, nor ergosterol
3.Drugs.
(1) polypeptide drugs: hydrophilic groups in the structure and the plasma membrane of phospholipids combined to increase its permeability (G – bacteria contain more phospholipids, so mainly effective for G – bacteria), such as polymyxin.
(2) polyene antifungal drugs: combine with ergocalciferol on the fungal plasma membrane to form “microporous” or “channel”, so that its permeability increases, such as amphotericin B.
Inhibit the synthesis of proteins.
1, bacterial ribosome (70S): 30S and 50S subunits, while the mammalian cell ribosome (80S): 40S and 60S composition.
2. Drugs.
(1) 50S subunit inhibitors: chloramphenicol, lincomycin, macrolides.
(2) 30S subunit inhibitors: tetracyclines.
(3) 30S subunit. Inhibitors of the whole process of protein synthesis: aminoglycosides.
3. The above drugs have no significant toxic effects on the protein synthesis process of host cells at constant doses
Inhibition of folic acid and nucleic acid metabolism: 1.
1, inhibition of tetrahydrofolate synthesis: inhibition of dihydrofolate synthase; methotrexate inhibits dihydrofolate reductase, thus inhibiting the synthesis of tetrahydrofolate, making nucleic acid metabolism impaired and inhibiting bacterial growth and reproduction, such as sulfonamides.
2. Inhibit DNA gyrase: hinder bacterial DNA replication and produce bactericidal effect, such as quinolone.
3, inhibition of DNA as a template for RNA polymerase: inhibit the beginning of RNA synthesis, mRNA synthesis to prevent bactericidal, such as rifampin.
Section III: Rational combination of drugs.
I. The purpose of the combination of drugs.
(1) to play a synergistic role to improve the efficacy of drugs
(2) to expand the antibacterial range of mixed infections or cases without bacteriological diagnosis
(3) To reduce the toxic side effects of drugs
(4) delay or reduce the occurrence of bacterial drug resistance
Second, the combination of drug indications.
(1) serious infections of unknown etiology: such as acute severe infections
(2) Single drug difficult to control serious infections: such as bacterial endocarditis
(3) Mixed infections that are difficult to control with a single drug: such as perforation of abdominal organs
(4) long-term use of drugs prone to drug-resistant bacterial infections: such as tuberculosis
(5) Combination of drugs to reduce the dose of the more toxic antibacterial drugs, reducing drug toxicity: for example, amphotericin B and flucytosine in the treatment of deep fungal infections, the former dose can be reduced, thereby reducing
(6) Infections at sites where drugs do not penetrate easily: e.g. penicillin + SD to prevent rheumatoid encephalitis, bacterial-induced osteomyelitis
Third, the results of the combination of drugs.
(1) synergistic effect (enhanced): 1 + 2 > 3
(2) additive effect: 1+2=3
(3) Unrelated effects: 1+2=2
(4) antagonism: 1 + 2 < 2
Fourth, how the correct combination of drugs.
(1) Drug classification.
Ⅰ reproduction period bactericidal drugs: penicillins, cephalosporins, vancomycin class
Ⅱ quiescent bactericidal drugs: aminoglycosides, quinolones, polymyxins
Ⅲ fast-acting antibacterial drugs: tetracyclines, chloramphenicol, macrolides
Ⅳ slow-acting antibacterial drugs: sulfonamides
(2) Effect.
Ⅰ + Ⅱ: synergistic Ⅱ + Ⅲ: additive or synergistic
Ⅰ + Ⅲ: antagonistic Ⅱ + Ⅳ: unrelated or additive
Ⅰ + Ⅳ: unrelated or additive Ⅲ + Ⅳ: additive
Section IV: Pharmacokinetic characteristics of antibacterial drugs
I. Classification
According to the antibacterial activity and effect duration of antibacterial drugs can be divided into three categories: concentration-dependent antibacterial drugs, short-acting – time-dependent antibacterial drugs and long-acting – time-dependent antibacterial drugs.
I. Concentration-dependent antibacterial drugs
1. Representative drugs: aminoglycosides, quinolones, amphotericin B, etc.
2, characteristics.
(1) The bactericidal effect depends on the peak concentration (Cmax) and is not closely related to the time of action. When the blood concentration reaches (8-10) × MIC, the maximum bactericidal effect is achieved.
(2) There is a first exposure effect (first exposure effect).
(3) There is a longer antibiotic after effect (refers to the bacteria and antibacterial drugs after a short contact, the drug concentration fell below the minimum inhibitory concentration (MIC), the growth of bacteria are still subject to sustained inhibition effect).
3, drug regimen: increase the drug dose, the frequency of administration once a day. Some drug toxicity is associated with peak concentrations and blood concentrations should be monitored, such as aminoglycosides.
Second, short-acting – time-dependent antibacterial drugs
1, representative drugs: most β-lactams, some macrolides, lincomycin, etc.
2, characteristics.
(1) The antibacterial effect of the drug is closely related to its contact time with bacteria, and the blood concentration can be reached as long as the MIC.
(2) Very short PAE.
(3) No first contact effect.
3, dosing regimen: continuous intravenous dosing or multiple dosing, that is, T > MIC at least in (40% to 50%) dosing interval to provide the most optimal efficacy and produce the lowest bacterial resistance.
Third, the long half-life of time-dependent antibacterial drugs
1, representative drugs: macrolides in the azithromycin, carbapenems, glycopeptides and azole antifungal drugs.
2, characteristics.
(1) The bactericidal effect depends on the effective blood concentration and is closely related to the time of drug contact with bacteria, while the relationship with Cmax is small. In 4 × MIC, the bactericidal effect will reach the degree of saturation.
(2) These drugs have a long PAE.
(3) No first contact effect.
3, dosing regimen: appropriate increase in drug dose to prolong and maintain the effective blood concentration of drugs for a longer period of time rather than Cmax.
Second, the oral absorption characteristics of antibacterial drugs
1.Fluoroquinolones, clindamycin, cefadroxil, cefradine, chloramphenicol, metronidazole, rifampin, isoniazid, compound sulfamethoxazole, flucytosine, etc. can absorb 80-90% of the administered dose after oral administration.
2, penicillin and ampicillin oral absorption of 10 ~ 20% and 30 ~ 50%, respectively.
3. Aminoglycosides, vancomycin, polymyxin, amphotericin B, etc. are little or no absorbed orally.
Three, the distribution characteristics of antibacterial drugs in the body tissue
(A) Distribution in the prostate tissue
1. The concentration of antibacterial drugs in prostate tissue and prostate fluid is mostly low.
2, fluoroquinolones, erythromycin, methotrexate, tetracycline, etc. in the prostate fluid and its tissues, most of them can reach the effective concentration.
(B) Distribution in the cerebrospinal fluid
1, meningeal inflammation or no inflammation, cerebrospinal fluid drug concentration can reach the level of inhibition (>MIC): chloramphenicol, sulfamethoxazole, sulfadiazine, meprobamate, metronidazole, meloxicillin, laxative cephalosporin, pyrazinamide, isoniazid, rifampin, ethambutol, acyclovir, acepromazine, fluconazole.
2. In meningitis only, the cerebrospinal fluid drug concentration reaches the level of inhibition (>MIC): penicillin, ampicillin, carbenicillin, ceftizoxime, ceftazidime, ceftriaxone, cefotaxime, cefuroxime, cefoxitin, aminoglutethimide, tetracycline, ofloxacin, ciprofloxacin, pefloxacin, vancomycin, amikacin, etc.
(iii) Distribution in the thoracoabdominal cavity
The drugs that penetrate into the thoracic and abdominal cavities are: ampicillin, cefazolin, cefadroxil, cefotaxime, cefoperazone, ceftriaxone, clindamycin, vancomycin, ofloxacin, ciprofloxacin, chloramphenicol, tetracycline, SMZco, etc.
(iv) Distribution in breast milk
1, the milk drug concentration ≥ 50% of the maternal serum drug concentration are.
Sulfonamides, TMP, isoniazid, erythromycin, clindamycin, chloramphenicol, tetracycline, aminoglycosides, ampicillin, carbenicillin.
2, milk drug concentration < 25% of the maternal serum drug concentration are.
Cefazolin, cefoxitin, cefuroxime, cefotaxime, cefoperazone, aminotrans, benzocillin, meloxicillin, aloxacillin, ceftriaxone, metronidazole, penicillin
(E) Drugs that can transmit through the placenta
1.Fetal blood concentration reaches 50-100% of maternal blood concentration: chloramphenicol, tetracycline, carbenicillin, sulfonamides, TMP, furantoin, and ofloxacin.
2, fetal blood concentration of maternal blood concentration of 30-50% of the drugs are: gentamicin, kanamycin, streptomycin, erythromycin, etc.
3.Drugs that can be used throughout pregnancy: penicillins, cephalosporins (except ceftriaxone), other β-lactams, macrolides (except esterified), lincomycin, phosphomycin.
(VI) Distribution in bile
1.The drugs with bile/serum concentration ratio > 10 are: cefoperazone, ceftriaxone, meloxicillin, piperacillin, doxycycline, erythromycin, etc.
2. drugs with bile/serum concentration ratio > 1 are: cephalexin, cefminoxime ampicillin-sulbactam, meloxicillin-sulbactam, cefalexin, cefamandole, cefotiam, metronidazole, clindamycin, rifampicin, meperidine.
3.The drugs with bile/serum concentration ratio ≥ 0.5 are: penicillin, carbenicillin, cefazolin, vancomycin, cefmetazole, cefoxitin, aminotril, etc.
4.The drugs with bile/serum concentration ratio < 0.5 include: cefuroxime, cefotaxime, ceftizoxime, gentamicin, tobramycin, amikacin, chloramphenicol
(VII) Distribution in bone tissue
1.Highly distributed drugs include: quinolones, teicoplanin, macrolides, rifampicin and methotrexate.
2.Medium distribution drugs are: second and third generation cephalosporins, aminoglycosides, clindamycin, fosfomycin, vancomycin, acylurea penicillin (meloxicillin).
3, low distribution are: the first generation of cephalosporins, ampicillin.
Section V. Bacterial drug resistance
I. Concept.
1, drug resistance: refers to the pathogen or tumor cells to repeatedly applied chemotherapeutic drugs to reduce the sensitivity or disappearance of the phenomenon.
(1) inherent resistance: based on the mechanism of action of the drug, by the bacterial chromosome genetic decision and the generation of resistance (enterobacteria to penicillin resistance)
(2) Acquired resistance: a bacteria does not have inherent resistance to a certain antimicrobial drug, but the resistance gene is acquired (mostly by plasmid-mediated, but also by chromosome-mediated resistance, such as the resistance of Staphylococcus aureus to penicillin)
Second, the mechanism of bacterial resistance generation.
1, reduce the permeability of the cell membrane: so that drugs are not easy to enter the body (bacteria to b-lactams, tetracycline resistance)
2, the production of inactivating enzymes: bacteria produce enzymes that change the structure of drugs
(1) hydrolase: b-lactamase. Such as penicillin type, hydrolysis of penicillins; cephalosporin type: hydrolysis of cephalosporins and penicillins.
(2) aminoglycoside synthases (passivases): acetylases, phosphorylases, nucleosidases, which can catalyze the binding of certain groups to the hydroxyl or amino groups of antibacterial drugs to inactivate the aminoglycosides
3.Change the structure of the target site.
(1) reduce the affinity of the target protein to the antimicrobial drug: such as RFP-resistant bacteria RNA multimerase b-subunit structure changes caused by drug resistance
(2) Increase the number of target proteins: e.g., methicillin resistance in Staphylococcus aureus
(3) Synthesis of alternative target proteins with low affinity for antimicrobial drugs but with the same function: e.g. PBP2A, a penicillin-binding protein produced by S. aureus, has very low affinity for β-lactam antibiotics resulting in drug resistance
4, drug active efflux system activity is enhanced: so that the rate of drug excretion is greater than the rate of endocytosis, reducing the concentration of drugs in the average body (such as quinolones, macrolides, etc.)
5, change the metabolic pathway: such as sulfonamide resistant bacteria produce PABA themselves or directly use folic acid to convert to dihydrofolate.