With the widespread clinical use of antibiotics, how to carry out the rational use has also become a more prominent problem, here the classification characteristics and application of antibiotics in respiratory medicine is summarized below.
I. Classification and characteristics of antibiotics
The commonly used antibiotics include β-lactams, aminoglycosides, macrolides, lincomycin, peptides, quinolones, sulfonamides, antituberculosis drugs, antifungal drugs and other antibiotics.
1, β-lactams such as these belong to the reproductive phase of fungicides. Its characteristics are: high blood concentration, broad antibacterial spectrum and low toxicity. Including penicillins, cephalosporins, new β-lactams and β-lactams and β-lactamase inhibitors composed of a composite preparation.
(1) Penicillins include acid-intolerant penicillins (penicillin G, procaine penicillin G, penicillin V potassium tablets), acid-resistant penicillins (benzathine penicillin, chlorazathine penicillin, dicloxacillin and fluorochlorine penicillin), broad-spectrum non-resistant pseudomonas (ampicillin, amoxicillin), broad-spectrum anti-pseudomonas (carbenicillin, furazacillin, ticarcillin, piperacillin, aloxacillin, meloxicillin) and anti-G-bacterial agents. (carbenicillin, furabancillin, ticarcillin, piperacillin, aloxacillin, meloxicillin) and anti-G-bacteria (methicillin, timocillin).
Penicillin G is mainly used clinically for pneumococcal, hemolytic streptococcal and anaerobic infections, to which Staphylococcus aureus and H. influenzae are mostly resistant. Procaine penicillin G has a longer half-life than penicillin. Penicillin V potassium tablets are acid-resistant, can be taken orally and are easy to use.
②Dicloxacillin has the strongest antibacterial activity against acid-producing penicillin G-resistant Staphylococcus aureus, is worse than penicillin G against other G+ cocci, and is ineffective against methicillin-resistant Staphylococcus aureus (MRSA).
③Amoxicillin antibacterial spectrum and ampicillin similar, pneumococcus, hemolytic streptococcus, enterococcus and influenzae bacteria are sensitive to this drug, antibacterial effect is better than ampicillin, but not effective for pseudomonas.
The antimicrobial effect of broad-spectrum anti-Pseudomonas class is similar to that of penicillin G. It has strong antimicrobial effect on G-bacteria (such as Escherichia coli, Streptococcus pyogenes, S. influenzae, etc.) and Pseudomonas, especially piperacillin, aloxacillin and meloxicillin have stronger antimicrobial activity.
⑤ Anti-G-bacillus class is only used for anti-G-bacillus, not for G+cocci and Pseudomonas.
(2) Cephalosporins are broad-spectrum antibacterial drugs, divided into four generations. The first and second generation are ineffective against Pseudomonas aeruginosa, some varieties of the third generation and the fourth generation are effective against Pseudomonas aeruginosa, and these drugs are ineffective against Mycoplasma and Legionella.
①The first generation cephalosporins include cefothiophene, cefadroxil, cefazolin and cefradine. The antibacterial activity against acid-producing Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus haemolyticus and other G+ cocci is stronger than the second and third generations, and the effect on G- bacilli is much less than the second and third generations, and only a few enterobacteria have an effect. It has poor stability to β-lactamase and has some toxicity to kidney. It is ineffective against Pseudomonas aeruginosa, Proteus mirabilis and Bacillus immobilis. Among them, cefazolin and cefradine are more commonly used.
②Second generation cephalosporins include cefuroxime, cefaclor, cefamandole, cefotiam, cefmetazole, cefoxitin, etc. The antibacterial activity against G+ cocci including acid-producing Staphylococcus aureus is similar to or slightly weaker than the first generation, and stronger than the first generation against G- bacilli, but not as strong as the third generation, and has strong antibacterial activity against influenza bacilli, especially cefuroxime and cefamandole, but not effective against Pseudomonas aeruginosa, Serratia marcescens, Bacillus cereus and Bacillus immobilis. Except for cefamandole, it is stable to β-lactamase.
③Third generation cephalosporins include ceftazidime, ceftazidime, cefotaxime, cefoperazone, cefdizime, cefmetime, cefixime, etc. They have certain activity against acid-producing Staphylococcus aureus, but are weaker than the first and second generations. They have strong antibacterial activity against G-organisms including Serratia marcescens and Pseudomonas aeruginosa, among which ceftazidime has a broader antibacterial spectrum and the strongest effect against Pseudomonas aeruginosa, followed by cefoperazone. Cefdizime is ineffective against Pseudomonas aeruginosa, Bacillus immobilis and Enterococcus-like bacteria. Except for cefoperazone, it is stable to β-lactamase and nephrotoxicity is rare.
④ Fourth-generation cephalosporins include cefpirome, cefepime, cefazolin, etc. The antibacterial effect is fast, the antibacterial activity is stronger than the third generation, and it has considerable activity against G+ cocci including acid-producing Staphylococcus aureus. It is similar to the third generation against G- bacilli including Pseudomonas aeruginosa. The activity against drug-resistant strains exceeds that of the third generation. Cefpirome is superior to ceftazidime against G-rods including Pseudomonas aeruginosa, Serratia marcescens, and Clostridium perfringens. Cefepime is significantly more effective against G+ cocci and is sensitive to this product except for Flavobacterium and anaerobic bacteria. It is more stable to β-lactamase.
(3) New β-lactams include carbapenems (imipenem, panipenem, meropenem) and monocyclic β-lactams (aminoglutethimide, carumonan). TENA (imipenem/cilastatin) has an extremely broad antibacterial spectrum, with strong antibacterial activity against G-, G+ and anaerobic bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis and Bacteroides fragilis, which are resistant to other antibiotics, and its activity against most resistant bacteria exceeds that of third-generation cephalosporins. It is highly stable to various β-lactamases. Aminotransim has good antibacterial effect on most G-bacteria including Enterobacteriaceae and Pseudomonas aeruginosa, but it is ineffective against G+cocci and anaerobic bacteria, and stable against β-lactamases.
(4) β-lactamase inhibitors and β-lactams composed of a composite preparation of β-lactamase inhibitors can be produced with bacteria β-lactamase line suicide binding, thereby protecting β-lactam from β-lactamase hydrolysis, continue to play antibacterial effect. Clavulanic acid, sulbactam and tazobactam are commonly used β-lactamase inhibitors in clinical practice. They form a compound preparation with β-lactams, which can enhance the bactericidal effect on drug-resistant strains and expand the antibacterial spectrum. (cefoperazone plus sulbactam) and tazocillin (piperacillin plus tazobactam).
2, aminoglycosides such as these are stationary fungicides. Commonly used are amikacin, tobramycin, gentamicin, netilmicin, cisomicin and streptomycin. Mainly anti-G-bacteria, including Pseudomonas aeruginosa, Enterobacteriaceae, Serratia marcescens, Bacillus immobilis, etc. Amikacin has the strongest effect. Anti-G+cocci also have some activity, but not as strong as the first and second generation cephalosporins. The antibacterial activity against Staphylococcus is strongest with netilmicin, and the best against Mycobacterium tuberculosis with streptomycin. It is not effective against anaerobic bacteria. Such drugs have toxic effects on the auditory nerve and kidney, the use of certain restrictions.
3, macrolides are narrow-spectrum fast-acting antibacterial agents, antibacterial spectrum and penicillin G similar, mainly for aerobic G + cocci, G – bacilli and anaerobic cocci. Legionella, Mycoplasma, Chlamydia and some influenza bacilli are sensitive to this class of drugs. It is not effective against Pseudomonas aeruginosa and most Enterobacteriaceae. The new macrolides, including roxithromycin, clarithromycin and azithromycin, do not have a significantly expanded antibacterial spectrum compared to erythromycin, but improved pharmacokinetics and reduced side effects are notable advances. Azithromycin is worse than erythromycin for G+ cocci and stronger than erythromycin for G- bacilli, especially for the common causative agents of socially acquired pneumonia (CAP), Mycobacterium influenzae, Mycoplasma, Chlamydia and Legionella, and can be the first choice for CAP treatment.
4, tetracyclines are broad-spectrum antibiotics. Because of the common pathogenic bacteria have been resistant, now only used for mycoplasma, chlamydia, rickettsia and legionella infection, doxycycline and minocycline antibacterial spectrum with tetracycline, but the antibacterial effect is 5 times stronger than tetracycline, the latter effect is stronger, effective for most MRSA.
5, lincomycin class including lincomycin, chlorine lincomycin, antibacterial spectrum is narrower, antibacterial effect is similar to erythromycin, chlorine lincomycin antibacterial activity is stronger than lincomycin 4-8 times, mainly used for Staphylococcus aureus and anaerobic bacterial infections.
6, polypeptides including polymyxin B, polymyxin E, vancomycin, desmethyl vancomycin and wall-mycin. Polymyxin B and E, nephrotoxic, poor efficacy, only for serious drug-resistant G-bacterial infections. Vancomycin and desmethylvancomycin are reproductive phase bactericides with high antibacterial activity against G+ cocci including multi-drug resistant Staphylococcus aureus, Streptococcus haemolyticus, Streptococcus pneumoniae and Streptococcus faecalis, and are mostly resistant to G- bacilli. Squamycin antibacterial spectrum and antibacterial effect is similar to vancomycin, but slightly worse for Staphylococcus epidermidis, and stronger than vancomycin for Enterococcus and Clostridium difficile.
7.Quinolones include norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, flurofloxacin, ilofloxacin, lomefloxacin, sparfloxacin, griseofulvin, lufloxacin, clindrofloxacin, barofloxacin, trevafloxacin, etc. Compared with ciprofloxacin and ofloxacin, the new quinolones have enhanced antibacterial activity against G+ cocci while maintaining good antibacterial activity against G-bacilli, with clindamycin and trevafloxacin being the strongest; antibacterial activity against G+ anaerobes has also been enhanced, with trevafloxacin being more than 10 times higher than metronidazole. The antibacterial activity of quinolones against G+ anaerobic bacteria is considered to be the strongest; the antibacterial activity against other common respiratory pathogens has also been improved to varying degrees, for example, the antibacterial activity of sparfloxacin against Mycobacterium tuberculosis is 4-8 times stronger than that of ciprofloxacin, and it has considerable activity against other branching bacteria, Legionella, Mycoplasma, Chlamydia and MRSA. It is mostly used clinically for nosocomial infections, especially for G-bacteria and MRSA infections that are resistant to other antibiotics. In recent years, the rate of bacterial resistance has been increasing, especially in Enterobacteriaceae, MRSA and Pseudomonas aeruginosa. This class of drugs can make bacteria cross-resistance between species, and resistance to other antibiotics, such as β-lactam drugs. Therefore, attention should be paid to the selection of indications when choosing. The new classification of quinolones is the original first and second generation together called the first generation, the representative drugs are nalidixic acid, pirperidic acid, antibacterial spectrum for G-bacteria, used for urinary tract and intestinal tract infections; the early development of fluoroquinolones in general called the second generation, the representative drugs are oxyfloxacin, ciprofloxacin, antibacterial spectrum for G-bacteria-based, used for various systemic infections; the third generation is based on the second generation to increase the The third generation is based on the second generation to increase the anti-G+coccus activity, the representative drugs are sparfloxacin and pastufloxacin, the antibacterial spectrum includes G-bacillus and G+coccus, used in various system infections; the fourth generation is based on the third generation to increase the anti-aerobic activity, the representative drugs are trevafloxacin and moxifloxacin, the antibacterial spectrum includes G-bacillus, G+coccus and anaerobic bacteria, used in various system infections. Compared with the second generation, the third and fourth generation mainly increase the antibacterial activity against G+coccus, anaerobic bacteria, mycoplasma, mycobacterium tuberculosis and legionella, which can be used as the first-line therapeutic drug for CAP.
8, sulfonamides commonly used are cotrimoxazole, mostly used for mild to moderate bacterial infections and chlamydial infections, is the drug of choice for Pneumocystis carinii.
9, anti-tuberculosis drugs commonly used are isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin. Isoniazid is the anti-tuberculosis drug of choice and is an all-purpose bactericidal agent for intra- and extracellular tuberculosis bacteria, which is more effective against reproductive phase bacteria and less effective against stationary phase bacteria. Rifampicin has strong antibacterial activity against M. tuberculosis, acting intra- and extracellularly in the reproductive and stationary phases, and is an all-purpose bactericidal agent. Pyrazinamide is a potent bactericidal agent in intracellular and acidic environments, and ethambutol has an inhibitory effect on reproductive phase bacteria. Isoniazid, rifampicin and pyrazinamide are the most important drugs to form the initial short-course chemotherapy regimen, and ethambutol (or streptomycin) can be involved in the composition of the short-course chemotherapy regimen. The combination of the above drugs can increase the efficacy and delay the development of drug resistance.
10.Antifungal drugs include amphotericin B, fluconazole, itraconazole and 5-fluorocytosine. Amphotericin B is the strongest broad-spectrum antifungal drug, despite its toxic side effects, but is still one of the drugs of choice for deep fungal infections, and has strong antibacterial activity against new Cryptococcus, Histoplasma, Coccidioides, Candida and Aspergillus. Fluconazole is a broad-spectrum antifungal agent with high efficiency against most of Candida spp., Cryptococcus flexneri and Sphaerococcus spp. etc., but it is ineffective against Aspergillus. Itraconazole is well absorbed orally, has a wide antibacterial spectrum, also has significant activity on Aspergillus, with small toxic side effects. 5-fluorocytosine has a narrow antibacterial spectrum, has strong antibacterial activity on new Cryptococcus, Candida albicans, and also has a certain effect on some Aspergillus, and amphotericin B or fluconazole can be used together to improve the efficacy and prevent drug resistance.
11, other antibacterial drugs such as fosfomycin, a wide antibacterial spectrum, but the antibacterial effect is not strong, low toxicity. Metronidazole and tinidazole have strong bactericidal effect on various specialized anaerobic bacteria, and their efficacy is significantly better than that of lincomycin, which is not effective for aerobic bacteria or parthenogenic anaerobic bacteria, and can be used in combination with other antibiotics to treat mixed infections.
Second, the rational application of antibiotics
1, application principles and methods of empirical drug selection should be made first sputum smear examination, can roughly determine the pathogen of infection is G + cocci or G – bacillus, so that the choice of antibiotics can be relatively targeted.
In socially acquired infections, the pathogens are pneumococci, hemolytic streptococci, Staphylococcus aureus, Legionella, anaerobic bacteria and viruses, mycoplasma and chlamydia, and erythromycin, tetracycline, penicillin G, ampicillin, cotrimoxazole, lincomycin and first-generation cephalosporins are often used.
In hospital infections, elderly people, patients with chronic obstructive pulmonary disease and immunosuppressed patients, G-bacteria (such as Enterobacteriaceae, Pseudomonas aeruginosa, immobile bacilli) and G+cocci are mainly Staphylococcus aureus and anaerobic bacteria, there are also fungi, tuberculosis and non-tuberculous branching bacilli and rare cytomegalovirus, Pneumocystis carinii, etc. Acid-resistant penicillins, broad-spectrum penicillins, first- to third-generation cephalosporins, imipenem, aminotrans, aminoglycosides, quinolones, vancomycin, and anti-anaerobic and antifungal agents are commonly used. Along with empirical treatment, pathogenic testing should be actively pursued. After three days of antibacterial treatment, if the clinical manifestations of pneumonia improve, suggesting the correct choice of regimen, continue the medication according to the original regimen. If the clinical manifestations do not improve or the condition worsens, the anti-infective drugs should be switched. Select drugs with high sensitivity, narrow antibacterial spectrum, low cost and low toxic side effects according to the results of drug sensitivity test. If there is no drug sensitivity result as a guide, drugs that can control common G-bacteria, Pseudomonas aeruginosa and G+cocci should be used, and anti-anaerobic drugs should be added for those with a history of aspiration or abdominal or pelvic infections. Try to use β-lactams with less toxic side effects, the dose should be sufficient, and the method of administration should be correct.
2, the combination of drugs and rational allocation of general bacterial infection with an antibiotic can be controlled, no need to combine drugs, but for the pathogenic bacteria unknown serious infections or patients with underlying disease complications of cardiopulmonary insufficiency, immune deficiency, or mixed infections, should take a combination of drugs, can play a synergistic effect, enhance the efficacy and reduce the generation of bacterial resistance.
The reasonable combination of drugs should be reproductive phase bactericides plus stationary phase bactericides, such as β-lactams plus aminoglycosides, can play a synergistic role; stationary phase bactericides accelerate the effect of bacteriostatic agents, such as aminoglycosides plus macrolides, have a cumulative synergistic effect; penicillins plus cephalosporins, can continuously inhibit the synthesis of bacterial cell walls, resulting in synergistic effects; fast-acting bacteriostatic agents and reproductive phase bactericides, such as macrolides The combination of fast-acting bacterial inhibitors and reproductive phase bactericides, such as macrolides and β-lactams, should not be used because fast-acting bacterial inhibitors can rapidly inhibit bacterial protein synthesis and prevent them from entering the reproductive phase, resulting in a weakened activity of reproductive phase bactericides and antagonistic effects.
Tylenol combined with piperacillin for the treatment of Pseudomonas aeruginosa infection can have an antagonistic effect because Tylenol induces the production of β-lactamase in bacteria, which inactivates penicillin with low enzyme resistance. After-effects of antibiotics and dosing intervalAfter-effects of antibiotics (PAE) refers to the contact between high concentration of drugs and bacteria, with the metabolism in the body, the drug concentration gradually decreases, when the concentration is lower than the MIC, antibacterial drugs can still continue to inhibit bacterial growth, this phenomenon is called PAE.Various antibacterial drugs have different degrees of PAE against G+cocci.But for G-bacilli, only aminoglycosides and quinolones But for G-bacilli, only aminoglycosides and quinolones have satisfactory PAE; carbapenems and fourth-generation cephalosporins have moderate PAE for G-bacilli, while penicillin and first, second and third-generation cephalosporins have almost no PAE.
The dosing interval of antibacterial drugs depends on the half-life of the drug, the presence or absence of PAE and its duration, and whether the antibacterial effect is concentration-dependent. The effect of time-dependent antibiotics depends mainly on the MIC time of the bacteria and is not related to the blood concentration, so the administration principle should shorten the interval to make the blood concentration higher than the MIC time of the pathogenic bacteria by at least 60% within 24h.
Time-dependent antibacterial drugs (bactericidal effect of non-concentration-dependent, no PAE or very short), the representative drugs are penicillins, the first, second and third generation cephalosporins and aminotrans, etc. The dosing method should shorten the dosing interval, preferably once every 6-8h, and try to extend the time when the blood concentration exceeds the MIC.
Concentration-dependent antibiotics (bactericidal effect has a concentration-dependent, with a better PAE), the representative drugs are aminoglycosides and quinolones, the method of delivery should increase the blood concentration, the appropriate extension of the dosing interval.
Between the concentration, time-dependent drugs ((bactericidal effect of non-concentration-dependent has a certain PAE), the representative drugs are carbapenems, fourth-generation cephalosporins, macrolides, lincomycin, vancomycin, etc., the drug delivery method between the above two.
In addition to pharmacodynamics, the dosing interval should also consider the relationship between the toxic side effects of the drug and the blood concentration. Aminoglycosides bactericidal effect is concentration-dependent, but its toxicity is not directly related to blood concentration, regardless of its half-life, for normal renal function, the daily dose of one application compared with divided into 2-3 applications, its efficacy is unchanged or better, while the renal and ototoxicity is reduced; for patients with reduced renal function, aminoglycosides should be given for the first time a half amount of 1 day to maintain the blood concentration in body fluids, followed by The daily dosage should be calculated by creatinine clearance and given in 2 doses. Also concentration-dependent quinolones, because their toxicity is related to blood concentration, except for drugs with a long half-life, generally do not take a daily application, most of them are given once every 12h.