Bacterial resistance has become a major problem in the treatment of clinical infectious diseases, and the irrational application of antibiotics is an important cause of bacterial resistance, and if we do not pay attention to this problem, we will have no drugs available in the near future. Therefore, the rational use of antibiotics is the common responsibility of each of our clinical medical workers.
I. Introduction
The latest development in antibiotic therapy is to guide the use of drugs according to their pharmacokinetics and pharmacodynamics. The so-called PK is the pharmacokinetics of antibiotics, which refers to the metabolic process of drug absorption, distribution and excretion in the body; the so-called PD is the pharmacodynamics of antibiotics, which refers to how the drug exerts its bactericidal effect in the body.
1. PK/PD of antibiotics: According to the PK/PD parameters of antibiotics, antibiotics can be divided into the following two main types: (1) concentration-dependent: the parameters for evaluating such drugs are: ① the ratio of the peak serum drug concentration (Cmax) and the minimum bacterial inhibitory concentration (MIC) of bacteria after dosing – Cmax/ MIC, when the ratio >8-10, the strongest antibacterial activity of these drugs; ② the ratio of the area under the curve (AUC) and the minimum bacterial inhibitory concentration (MIC) of serum drug after use – AUC/MIC (also known as AUIC), when the ratio >30 (gram-positive cocci) or >125 (gram-negative bacilli) Such drugs have the strongest antibacterial activity. (2) Time-dependent: The parameter for evaluating such drugs is: the percentage of time that the serum drug concentration is higher than the bacterial MIC during the dosing interval after administration (T>MIC), and the antibacterial activity of such drugs is strongest when >40%. 2. Antibacterial drugs are classified according to PK/PD as
(1) concentration-dependent antibiotics: the bactericidal effect on pathogenic bacteria depends on the peak concentration, such as aminoglycosides, fluoroquinolones, ketolactones, amphotericin B, etc. The main reference parameters are: AUC0-24/MIC (AUIC), Cmax/MIC.
(2) Time-dependent antibiotics: the antibacterial effect is closely related to the duration of action with bacteria, such as most β-lactams, lincomycin, oxazolidinones, and the main parameters are: T>MIC.
(3) Time-dependent but longer duration of antimicrobial activity: The antimicrobial activity of some drugs is related to both time and concentration and post-antibiotic effect (PAE), such as drugs that are mainly time-dependent but have PAE or longer elimination half-life (T1/2), such as streptomycin, tetracycline, carbapenems, glycopeptides, macrolides, azole antifungals, with the main parameters of T>MIC, PAE, T1/2, AUC/MIC.
Second, the quinolones antibacterial drugs
This class of drugs has many advantages, but also has many shortcomings, there is a certain tendency of abuse, should be noted: ① is a typical concentration-dependent antibiotics; ② usually the total dose should be given once.
1. New classification method of quinolones.
We refer to the third and fourth generation fluoroquinolones as neoquinolones because their antibacterial activity is expanded to positive cocci and their pharmacokinetics are characterized by extended half-life and increased AUC, which are more typical concentration-dependent antibacterial drugs and are more suitable for once-daily dosing. From the perspective of community respiratory infections, since their common pathogens are Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila, and the antimicrobial spectrum of third- and fourth-generation fluoroquinolones can cover these pathogens, they are also called respiratory quinolone antimicrobials.
2. PK/PD parameters for selecting quinolone antibacterial drugs: (1) To achieve the desired antibacterial effect: AUIC: for G- bacteria should be >100-125, G+ bacteria should be >30; Cmax/MIC should be >8-10, and to reduce resistance: Cmax/MIC should be >8-10. (2) AUIC is the key PK/PD parameter for concentration-dependent antibiotic efficacy, most used mainly to evaluate fluoroquinolones. (3) Quinolones antibacterial drugs: AUIC < 125, bacterial clearance < 30%; AUIC > 125, bacterial clearance up to 80%; critical value AUIC > 125; therefore, for G+ cocci, immunologically sound patients: AUIC ≥ 30; G-bacilli, immunologically compromised patients: AUIC ≥ 100 (125). (4) Cmax/MIC is also a key PK/PD parameter for concentration-dependent antibiotic efficacy, and is commonly used to evaluate the efficacy of aminoglycoside antibiotics: Cmax/MIC 8-12, clinical efficiency 90%; critical value: Cmax/MIC 10-12.
3.How to choose quinolones? (1) Moxifloxacin, levofloxacin, ciprofloxacin? –If the possibility of gram-positive cocci is considered, choose the fourth generation such as “moxifloxacin”; if the possibility of gram-negative bacilli is considered, choose the second generation such as “ciprofloxacin”; If it is difficult to determine which bacteria is more likely, choose “levofloxacin”. (2) Disadvantages of quinolones: relatively narrow antibacterial spectrum, relatively low blood concentration, bacterial resistance, adverse reactions and drug interactions.
①Quinolones that have been withdrawn from the market at present.
Quinolones withdrawn from the market due to adverse reactions
② common adverse reactions and drug interactions: general side effects: gastrointestinal reactions, rash, etc., central nervous system; side effects: phototoxicity – pefloxacin, sparfloxacin; articular cartilage toxicity; hepatotoxicity; cardiotoxicity; drug interactions: such as interactions with theophylline, non-steroidal anti-inflammatory drugs; other.
4, the use of quinolones: quinolones antibacterial drugs because of the typical concentration-dependent drugs, so the method of administration is usually given once a day, such as levofloxacin, according to the severity of the disease, you can use 0.3 / time, 0.5 / time, 0.75 / time, but are given once a day, regardless of oral or intravenous administration. The same is true for moxifloxacin, 0.4/dose, administered once daily, either orally or intravenously. The exception is ciprofloxacin, which is an early developed drug with a short elimination half-life, and still needs to be administered in divided doses, commonly 0.2/dose, once every 8-12 hours, and in severe cases 0.4/dose, once every 8-12 hours. 5. Irrational application of quinolones.
① for patients with previous central nervous system infection and a history of epilepsy; ② for children, pregnant and lactating women; ③ as a first-line anti-tuberculosis drugs; ④ when a quinolone is not effective, replace the use of another quinolone; ⑤ with aminophylline, caffeine and oral anticoagulants (Warfarin, etc.) at the same time (traditional quinolones); ⑥ with aluminum and magnesium salts containing acidulants and non-steroidal anti-inflammatory agents Combined use.
Third, β-lactam antibiotics such antibiotics generally have high blood concentration, wide antibacterial spectrum, strong bactericidal power, low toxicity, but should be noted: ① the increase of drug-resistant strains; ② lung tissue concentration is often only a fraction of the blood concentration, to avoid toxicity under the premise of increasing the dose; ③ is a typical time-dependent antibiotics, the total dose should be divided into doses; ④ attention to allergic reactions. (A) β-lactam antibiotics include penicillins, cephalosporins and atypical β-lactams. 1, penicillins: (1) natural penicillins: ① penicillin G: narrow spectrum, mainly for gram-positive cocci; ② enzyme-resistant penicillin: penicillin V, can be taken orally, produced in Germany; ③ natural penicillin long-acting preparations: procaine penicillin, benzathine penicillin G (long-acting cillin). (2) Penicillinase-resistant semi-synthetic penicillin: mainly used for penicillin G-resistant Staphylococcus aureus infection, but methicillin-resistant Staphylococcus aureus (MRSA) is not effective, ① methicillin (neocin Ⅰ); ② benzocillin (neocin Ⅱ); ③ ethenocillin (neocin Ⅲ); ④ cloxacillin (o-chloropenicillin); ⑤ flucloxacillin (flucloxacillin); ⑥ dicloxacillin (dicloxacillin). (3) Broad-spectrum semi-synthetic penicillin: enhanced effect on gram-negative bacteria, unstable to β-lactamase, ineffective to MRSA, there are four generations of products. ①First generation: aminopenicillin, broad spectrum, coccus, general bacillus, Pseudomonas aeruginosa ineffective: ① ampicillin; ② amoxicillin. ②Second generation: carboxy penicillin, expanded for gram-negative bacilli, effective for Pseudomonas aeruginosa, but the effect is not strong; for anaerobic bacteria have some effect. Ticarcillin. ③Third generation: urea-based penicillin, strong action against Pseudomonas aeruginosa; effective against anaerobic bacteria, and cocci: piperacillin. ④ Fourth generation: amidine-based penicillin, effective for negative bacilli, poor for positive cocci; resistant to Pseudomonas aeruginosa: methicillin. 2, cephalosporins: Cephalosporins antibiotics are a class of broad-spectrum semi-synthetic antibiotics, whose parent nucleus is 7-amino cephalosporanic acid obtained by cleavage of cephalosporin C, with the advantages of strong antibacterial action, resistance to penicillinase, high clinical efficacy, low toxicity, less allergic reactions than penicillins, etc. According to the antibacterial spectrum, stability to β-lactamase and antibacterial activity against Gram-negative bacilli, cephalosporins are currently divided into four generations.
(1) The first generation: good for Gram-positive bacteria, slightly stronger than the second generation, significantly stronger than the third generation; poor for Gram-negative bacilli, more ineffective for Enterobacteriaceae; poor stability for β-lactamase; certain toxicity to the kidney. Such as cefadroxil, cefazolin, cefradine, etc.
(2) Second generation: slightly worse or similar to the first generation for Gram-positive bacteria, stronger than the first generation for Gram-negative bacteria, but not as strong as the third generation, ineffective for Pseudomonas aeruginosa; more stable for β-lactamase; less toxic to kidney. Such as cefamandole, cefotiam, cefuroxime, cefaclor, cefprozil, etc.
(3) Third generation: weak effect on Gram-positive bacteria, strong antibacterial activity on Gram-negative bacteria, some varieties have strong effect on Pseudomonas aeruginosa; highly stable to β-lactamase; basically non-toxic to kidney. Such as cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefmenoxime, cefsulodin, cefodizime, cefpiramide, cefadroxil, cefdinir (oral), etc.
(4) Fourth generation: Compared with three generations of cephalosporins, the antibacterial spectrum is expanded, especially for G+ cocci, the blood concentration is increased, and the ability to cross the blood-brain barrier is increased; it is highly stable to β-lactamases, especially AmpC enzyme; it is currently recommended clinically for bacterial meningitis, hospital-acquired pneumonia, ventilator-associated pneumonia, sepsis, granulocyte deficiency co-infection and severe community-acquired pneumonia. Such as cefepime (cefpimet), cefpirome, cefazolin.
3, atypical β-lactam antibiotics (1) cephalosporins: antibacterial spectrum and the second generation of cephalosporins similar, the stability of β-lactamase is stronger than most cephalosporins; characterized by strong antibacterial activity against both aerobic and anaerobic bacteria. Such as cefoxitin, cefmetazole, cefotetan, ceflazone, cefminox. (2) Carbapenems: wide antibacterial spectrum, covering almost all common aerobic Gram-positive and negative bacteria (including Enterococcus and Pseudomonas, etc.) and anaerobic pathogens, with strong antibacterial activity. ①Imipenem (Imipenem, Tylenol): easily inactivated by renal dipeptidase, so need to add cistatin (renal dehydrogenase inhibitor, 1:1); ②Meropenem (Mepin): stable to renal peptidase, no need to add renal enzyme inhibitor; ③Panipenem (Kebenin): need to be combined with betamilon (1:1), the latter can reduce the accumulation of panipenem in renal tissue and reduce its nephrotoxicity; ④Biapenem (5) Dolidipenem. (3) Penicillin: Faropenem. (4) β-lactamase inhibitors and their compound: no or only weak antibacterial activity by itself; strong inhibition of β-lactamase produced by many bacteria. β lactamase inhibitors: ① Clavulanic acid (rod acid): only weak antibacterial activity; ② Sulbactam (penicillin sulfone): itself few antibacterial activity, enzyme inhibition is only 1/2 to 1/4 of rod acid, but it has a special effect, single drug is effective against pan-resistant immobile bacilli; ③ Tazobactam (triazobactam): enzyme inhibition strength is better than sulbactam and rod acid. β-lactam/enzyme inhibitor combination: ①clavulanic acid + amoxicillin (Amytin) (1:2~1:14) ②clavulanic acid + ticarcillin (Temetin) (1:30, 1:15) ③sulbactam + ampicillin (Ulixin) (1:2) ④sulbactam + cefoperazone (Sulphen) (1:1) ⑤triazobactam + piperacillin (Tegyxin) (1:8) ⑥sulbactam + (1:4) ⑦Sulbactam + amoxicillin (Tebamycin) (1:2, 1:1) ⑧Sulbactam + piperacillin (Termectin) (1:2) ⑨Sulbactam + meloxicillin (Hankwang) (1:4) ⑩Sulbactam + ceftazidime (11) Trizolbactam + ceftazidime (12) Trizolbactam + cefoperazone (Kesut) (1:4) (ii) β-lactam antibiotics -Pharmacodynamic parameters of time-dependent antibiotics
1. The critical value of T>MIC.
2. Maximization of %T>MIC: increase the amount per dose; increase the number of daily doses; extend the drip time or continuous dosing.
(C) the application method of β-lactam antibiotics ① time-dependent antibacterial drugs, the main point is T>MIC; so must be divided into doses, usually 6-8 hours once, and does not advocate Bid or Tid dosing method; only a few or mild disease can be 12 hours once, such as cefepime; only ceftriaxone and ertapenem due to a long half-life, mild patients can be given once a day. ②Change the method of administration; usually when antibiotics are given intravenously is about half an hour drip, such as extending the intravenous dosing time to 2-3 hours, can increase T>MIC, potentially increasing the efficacy and help to overcome the limitations of bacterial resistance. Some authors have also suggested that continuous intravenous administration can also increase the T>MIC of such drugs, such as meropenem, which is given as a loading dose followed by continuous intravenous pumping, which can also increase efficacy.
(iv) The irrational application of β-lactam antibiotics
(1) the third generation cephalosporins as the first choice for the treatment of “community-acquired pneumonia”; (2) the replacement of similar drugs when one drug is not effective; (3) the application of cefoperazone and other cephalosporins containing the side chain structure of methyl tetrazolium in patients with bleeding tendency; (4) the combination of cefazolin and aminoglycosides (such as amikacin) Combined application of cefazolin with aminoglycosides (e.g. amikacin) in elderly patients or patients with underlying renal insufficiency; ⑤ Not paying attention to the inquiry of penicillin allergy history, there is 10% cross-allergy between cephalosporin and penicillin; ⑥ Administering time-dependent β-lactam antibiotics in high doses once a day.