Need to change antibiotics if drug sensitivity suggests drug resistance?

Need to change antibiotics if drug sensitivity suggests drug resistance?  Empirical anti-infection is effective, drug sensitivity suggests drug resistance, can the antibiotics be changed?

In the process of treating infectious diseases, we sometimes encounter such situations:

Since the release of drug susceptibility results is often delayed, empirical anti-infective treatment is first performed after receiving patients, and clinical observations have shown that the treatment is effective, but later results of drug susceptibility tests show that the pathogen is “resistant” to previous empirical drugs ; Sometimes, empirical anti-infective treatment does not show obvious effect, but the results of drug sensitivity test show that the pathogenic bacteria are “sensitive” to the drug. Why is there such a paradox?

When the above-mentioned clinical practice is inconsistent with the results of drug sensitivity, it needs to be analyzed from the following aspects:

Concentration of bacterial liquid used for drug sensitivity test

For the drug susceptibility test of any bacteria, preparing the purified bacteria into an appropriate concentration of bacteria liquid is the basic guarantee for the correct result. If the concentration of the bacterial solution is too high, the bacteria will be resistant to all drugs; on the contrary, if the concentration of the bacterial solution is too low, it will appear that the bacteria are sensitive to all drugs.

According to the standards set by the World Health Organization (WHO), the concentration of the bacterial solution used in the drug susceptibility test should be about 150 million/mL.

Using a spectrophotometer to measure the absorbance of the fresh culture bacterial suspension to determine the bacterial concentration is the most accurate method. Most of the microbiology laboratories in tertiary A hospitals of the National Bacterial Resistance Surveillance Network use this method to determine the concentration of bacteria in drug susceptibility tests [1].

It is not difficult to see that if there is a problem with the preparation of the bacterial liquid used for the susceptibility test, it is very likely that the susceptibility test is inconsistent with clinical practice.

Judgment of pathogenic bacteria

Specimens with bacteria such as sputum, throat swabs, prostate fluid, feces, urine, negative swabs, etc., are difficult to avoid carrying bacteria during collection. Therefore, it is necessary to determine whether the bacteria are pathogenic bacteria or pathogenic bacteria. Carrying bacteria.

As the immunity of hospitalized patients usually declines, infections caused by conditional and non-pathogenic bacteria increase correspondingly [2]. If there are errors in the judgment of pathogenic bacteria, there may be inconsistencies between the drug susceptibility test and clinical practice.

For example, suppose we judge that Bacteria A is a pathogen, and the results of drug susceptibility test are also sensitive. But in fact, the real pathogenic bacteria are B bacteria, and they are resistant to the antibacterial drugs being used. In this way, we “self-righteous” chose a drug that has been tested by drug sensitivity tests, but the final result can only be-clinically proven ineffective!

Differential distribution of drugs in the body

The drug susceptibility standards of the American Committee for Clinical Laboratory Standardization (CLSI) are based on the relationship between the highest concentration (Cmax) in the blood and the minimum inhibitory concentration (MIC) of the drug after entering the body:

Cmax/MIC = 4～8 is sensitive (S);

Cmax/MIC = I～2 is the degree of intermediary (I);

Cmax/MIC <I is drug resistance (R).

Although the Cmax/MIC ratio of different drugs is not exactly the same as the above figures when judging the sensitivity level of different drugs, there is one factor that is consistent, that is, the standards are based on blood drug concentration (currently CLSI has not yet developed local infection Drug susceptibility criteria).

After the antibacterial drug enters the body, the concentration in the blood may be quite different from the concentration in other body fluids or tissues.

For example, the concentration of cefoperazone in the bile after 1 to 3 hours is 100 times the blood concentration, the concentration of ciprofloxacin in the urine can reach 200 mg, which is 50 times the blood concentration, and the concentration of levofloxacin in the kidney tissue is the blood concentration. 2 to 5 times of [2].

If the infection happens to occur in the above-mentioned high drug concentration site, then we judge the sensitivity according to the standards established by CLSI, and we will not be able to obtain consistent results of in vitro drug sensitivity and in vivo efficacy.

The difference between in vitro drug sensitivity test and in vivo drug metabolism environment

The efficacy of antibacterial drugs in vivo is related to the following PK/PD (pharmacokinetics and pharmacodynamics) parameters.

For concentration-dependent drugs such as aminoglycosides and quinolones, the parameter related to efficacy is AUC/MIC, which is the area under the curve:

When the drug susceptibility report is sensitive (S), it means that the clinical effect can be obtained with conventional dose treatment;

The drug susceptibility report is the intermediate degree (I), which means that increasing the dose or concentration of the drug can be effective;

Drug susceptibility report drug resistance (R), indicating that the drug has no effect.

Time-dependent antibacterial drugs, such as β-lactams, macrolides, clindamycin, glycopeptides, etc., need to meet T>MIC, that is, more than 50% of the time between two medications The blood concentration of the drug is higher than the MIC value to achieve clinical efficacy. However, some drugs in the current relationship between breakpoints and doses cannot achieve the unity of breakpoints, doses, and efficacy.

Taking cefotaxime as an example, the American Committee for Clinical Laboratory Standardization (CLSI) judges the MIC standards as follows: ≤ 8 (sensitive S), 16-32 (intermediate degree I),> 64 (resistance R).

However, some studies have shown that if the medication is used according to the CLSI judgment standard, it cannot reach the standard of T>MIC greater than 50% (the time between two medications). Only when the criteria for judging MIC are modified to ≤ 1 for sensitivity (S), 2 for intermediate degree (I), 4 for drug resistance (R), and a dose of 1 g/q8 h, can there be clinical effects.

In other words, for drugs such as ceftizoxime and ceftriaxone, if we use the drugs according to the CLSI criteria, the results of the drug sensitivity test may show that they are sensitive and can be treated with conventional doses, but the result is The inconsistency of breakpoints, doses, and curative effects ultimately did not receive good clinical curative effects.

Drug susceptibility testing is at odds with clinical practice. How to choose?

In the previous discussion, we have roughly known the possible reasons for the inconsistency between drug sensitivity testing and clinical practice. So, in our clinical work, how should we deal with such a situation? Do I need to make corresponding adjustments to the previously used drugs?

In general, there may be the following four relationships between drug sensitivity testing and clinical practice:

1. The results of drug susceptibility test show sensitivity and clinical practice is effective;

2. The results of drug susceptibility tests show drug resistance, and clinical practice is invalid;

3. The results of drug susceptibility tests show drug resistance, and clinical practice is effective;

4. The results of drug susceptibility test showed sensitivity and clinical practice was invalid.

On the one hand, the results of the drug susceptibility test may be affected by factors such as the culture medium, the drug susceptibility paper, the purity of the bacteria, the concentration of the bacterial solution, and the distribution of the bacterial solution on the culture medium [1]; on the other hand, as mentioned above , Our standard for judging whether the drug is sensitive or not has certain limitations, or is artificial.

When using the drug sensitivity test report to guide clinical medication, the influence of irrelevant factors on the drug sensitivity test should be minimized. Under this premise:

For the first case, the previous treatment can be continued without adjustment [4].

For the second situation, in principle, it is necessary to make adjustments to the previously used drugs, and use drugs that are sensitive to the drug sensitivity test [4].

For the third situation, the reason needs to be analyzed: if the result of the drug sensitivity report itself has problems and is false negative, there is no need to adjust the currently used drugs; if the result of the drug sensitivity test report is relatively objective, then as described above As mentioned, the criteria for judging whether drugs are sensitive or not we rely on is inherently artificial and not an absolute standard. When clinical treatment is effective, there is no need to adjust drugs. Clinical practice is the only criterion for testing truth.

For the fourth situation, we need to be cautious. In the case of relatively objective drug sensitivity test results, this situation may also be related to the following factors [4]:

(1) Antibacterial drugs cannot reach the lesion, and cannot reach the effective drug treatment concentration;

(2) The treatment time is too long, the bacteria in the body have developed resistance to antibacterial drugs, or the bacteria cultured in vitro have been effectively controlled as inferior bacteria in the body, and other kinds of dominant bacteria have become new pathogenic bacteria;

(3) In vitro tests cannot fully represent the body. Due to the objective existence of individual differences, the pharmacokinetics and pharmacodynamics of the drug in different patients cannot be completely consistent. The reason for the failure of the treatment may be that the patient is not sensitive to the drug. ；

(4) There may be other infection factors. After eliminating the possible interfering factors, the clinical treatment has no effect, then you can consider changing the treatment drug.

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