Lower respiratory tract infections usually refer to pneumonia and bronchitis, which are heavier and more dangerous than upper respiratory tract infections, while the distribution of pathogens is also very different from upper respiratory tract infections, and there are relatively few viral infections, so the application of antimicrobial drugs in lower respiratory tract infections becomes more important based on the above characteristics.
I. Community-acquired pneumonia
(A) Causing bacteria
Community-acquired pneumonia refers to pneumonia acquired outside the hospital. The most important causative agents of community-acquired pneumonia are Streptococcus pneumoniae and Haemophilus influenzae, which together account for approximately 40% to 80% of the cases. The distribution of these two pathogenic bacteria varies with country and region. The growth conditions of these two bacteria are demanding and not easy to culture, and if antibacterial drugs have been applied before taking the specimen, the positive rate will be significantly reduced, and the isolation rate of them in our hospitals is very low. Moreover, for these two bacteria, the exact prevalence, regional differences, drug resistance, etc. are still unclear, which is one of the problems faced by clinical workers and microbiologists together.
Recently, the increase of penicillin-resistant Streptococcus pneumoniae (PRSP) has attracted worldwide attention, and the prevalence of penicillin-resistant Streptococcus pneumoniae is very serious in our neighboring countries and regions, South Korea, Japan, Taiwan, and Hong Kong. For example, in Korea, the number of penicillin-insensitive Streptococcus pneumoniae (PRSP+PISP) had reached 73% in 1995.
The distribution of penicillin-resistant Streptococcus pneumoniae is different in different countries and regions. It is relatively rare in Australia, Northern Europe and India, and it is relatively rare in our country compared to neighboring countries. In Europe, the resistance rate is generally high in some countries in southern Europe.
Our country has a very high dosage of penicillin, but the resistance rate of bacteria is relatively low. The exact reason for this phenomenon has not been found yet, and it is estimated that it may be related to our doctors’ habit of applying high doses of penicillin. Because penicillin is applied in low doses or intramuscularly, bacteria can easily develop resistance.
Two years ago, the results of a nationwide survey on bacterial resistance showed that the number of Streptococcus pneumoniae insensitive to penicillin was about 20%. It is worth noting that the drug resistance of Streptococcus pneumoniae varies somewhat in different populations, with the resistance rate generally higher in children than in adults, and the resistance rate of Streptococcus pneumoniae carried by healthy people is higher than that of bacteria isolated from patients. Especially in kindergartens, the rate of drug resistance of Streptococcus pneumoniae isolated from the respiratory tract of children is higher, but in adults, the rate of drug resistance of Streptococcus pneumoniae isolated from the respiratory tract of patients with community-acquired pneumonia is not very high.
(ii) Antibiotic therapy
The drug resistance rate of Streptococcus pneumoniae in China is relatively low. Experts believe that the PRSP in China is not yet more than 4%, but penicillin-mediated Streptococcus pneumoniae (PISP) is increasing rapidly. For PRSP, third generation cephalosporins or fourth generation quinolones should be preferred, while for PISP it can be effective as long as the dosage of penicillin is increased.
Based on the above, and considering the affordability of underdeveloped areas in China, the Chinese Medical Association Respiratory Disease Section still lists penicillin G as the first-line drug of choice for empirical treatment of community-acquired pneumonia.
Considering the prevalence of atypical pathogens and the increased activity of the new macrolides against Haemophilus influenzae, it is recommended that macrolides may be preferred for community-acquired pneumonia. Some experts believe that Streptococcus pneumoniae in China is severely resistant to macrolides (40-50%) and should not be the first choice, but tissue concentrations of macrolides are much higher than blood concentrations, and further studies are needed to determine whether the in vitro MIC criteria can truly reflect the in vivo efficacy. In elderly or severe community-acquired pneumonia, macrolides in combination with β-lactams may be used as empirical therapy, with the aim of covering typical and atypical pathogens.
In patients with community-acquired pneumonia who are critically ill, elderly, have underlying metabolic disease, or have very severe manifestations of pneumonia, a combination of lactams and macrolides is advocated.
II. Hospital-acquired pneumonia
Compared with community-acquired pneumonia, the causative agents of hospital-acquired pneumonia are mainly Gram-negative bacilli (60-90%), followed by Streptococcus pneumoniae, Staphylococcus aureus, anaerobic bacteria, fungi, and atypical pathogens.
(A) Pneumonia caused by ESBLs-producing gram-negative bacilli
The main bacteria producing ultra broad-spectrum β-lactamases (ESBLs) are Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, etc. These bacteria are also common causative agents of hospital-acquired pneumonia. ESBLs are plasmid-mediated and are more easily transmitted.
The prevalence of ESBLs-producing bacteria is now better monitored in China. Generally speaking, the earlier and more the third-generation cephalosporins are applied, the higher the isolation rate of ESBLs-producing bacteria is, with Klebsiella pneumoniae and Escherichia coli in the range of 10-45 ％. Therefore, third-generation cephalosporins are not recommended even if they are sensitive in vitro, and fourth-generation cephalosporins are generally not recommended, but are still controversial. Early developed β-lactam antibiotics/β-lactamase inhibitors are not highly sensitive and have high intermediaries, but increased doses may still be effective. There are also newer agents such as cefoperazone/sulbactam and piperacillin/triazobactam that can achieve sensitivities of more than 60% against ESBLs-producing bacteria. For the treatment of severe ESBLs-producing bacterial infections, such as pneumonia with shock and pneumonia with sepsis, early use of cephalosporin antibiotics and carbapenem antibiotics is advocated. In addition to these drugs, for ESBLs-producing bacterial infections, drugs other than β-lactam antibiotics can be chosen for treatment. Because β-lactamases, including ultra-broad-spectrum enzymes, destroy β-lactam antibiotics and do not destroy antibiotics other than β-lactams, such as quinolones and aminoglycosides, non-β-lactam antibiotics can be chosen.
From the above table, it can be seen that the antibacterial activity (MIC) of some combination agents that started to be applied late such as piperacillin/tazobactam and cefoperazone/sulbactam against ESBLs-producing Escherichia coli and Klebsiella pneumoniae is still relatively satisfactory, while drugs that have been applied for a longer time have different degrees of resistance. There are two main reasons why ESBL-producing bacteria are resistant to enzyme inhibitors, one of which may be related to the large production of ESBLs and the relatively insufficient dose of enzyme inhibitors, when, for example, increasing the dose of drugs may still be effective. Another reason is that enzyme inhibitors are also β-lactam antibiotics, and some bacteria can produce enzymes that specifically destroy enzyme inhibitors, resulting in the failure of enzyme inhibitors.
(B) Pneumonia caused by AmpC enzyme producing bacteria
AmpC enzyme is also called cephalosporinase, named because it can hydrolyze cephalosporins. In the case of pneumonia caused by AmpC enzyme-producing bacteria, treatment may be more difficult than in the case of pneumonia caused by ESBLs-producing bacteria.
Isolation of AmpC enzyme or ESBLs-producing strains of Enterobacter cloacae (n=106)
The above table shows the isolation of 106 strains of Enterobacter cloacae. All Gram-negative bacilli, have the ability to produce AmpC enzymes, only the amount varies, and the results may all be positive when tested with PCI. However, only bacteria with high AmpC enzyme production are clinically referred to as AmpC enzyme-producing bacteria, and the inducible AmpC enzyme in the table above tends to be low-producing. From these 106 strains of Enterobacter cloacae, we can see that there are 3 strains (2.8%) that produce ESBLs alone; if we consider the bacteria that produce inducible AmpC enzyme plus ESBLs as the bacteria that produce ESBLs alone, there are 11 strains (10.4%) that produce ESBLs together; there are 17 strains (16%) that produce high AmpC enzyme alone; there are 14 strains that produce both high AmpC enzyme and The number of bacteria that produced both AmpC and ESBLs was 14, accounting for 13.2%. There were 4 strains that did not produce both enzymes, including low and no production.
Enzyme production in 42 strains of Enterobacter cloacae resistant to third-generation cephalosporins or aminotransferase
Among the bacteria, 11 strains (26.2%) were ESBLs-producing and ESBLs-producing plus AmpC enzyme-producing combined, 17 strains (40.5%) were high AmpC enzyme-producing, and 14 strains (33.3%) were high in both enzymes.
From the above results, it can be seen that the third generation cephalosporins are not sensitive to AmpC enzyme-producing bacteria and should be avoided; the most important difference between the fourth generation cephalosporins and the third generation is that they are effective against AmpC enzyme-producing bacteria and their use is advocated; in addition, carbapenem antibiotics and non-β-lactam antibiotics are both effective against AmpC enzyme-producing bacteria.
(iii) Determination of ESBLs or AmpC enzyme-producing bacteria
Three groups of Enterobacter cloacae were tested for in vitro antibacterial activity with different antibiotics, and the results showed that the first group, Enterobacter cloacae, was resistant to cefoperazone, moderately resistant to ceftazidime, and sensitive to both cefmetazole and cefoperazone/sulbactam; the second group, Enterobacter cloacae, was resistant to cefoperazone, ceftazidime, cefmetazole and ticarcillin/clavulanic acid, moderately resistant to cefoperazone/sulbactam, and sensitive to The third group of Enterobacter cloacae was resistant to ceftazidime, ceftriaxone, cefoxitin, cefoperazone/sulbactam and cefeprime and sensitive to imipramine.