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How to use antibiotics against infection?
How to use antibiotics against infection? At present, more than half of ICU patients still receive antibiotics when it is uncertain whether they have an infection.
ICU uses a large number of antibiotics. This behavior disrupts the ecological balance and promotes the spread of multi-drug resistant bacteria to a certain extent. At present, more than half of ICU patients still receive antibiotics when it is uncertain whether they have an infection. Clinicians implement the Antibiotic Management Program (ASP), which can avoid insufficient anti-infection and reduce the use of antibiotics.
In the ICU antibiotic use group, it is necessary to consider”
- 1. Which patients are prone to multi-drug resistant bacteria infection;
- 2. How to diagnose infection more accurately
- 3. How to choose monotherapy or combination therapy;
- 4. Manage the use of antibiotics through PK/PD concepts Dosage and method
- 5. How to evaluate the effectiveness of antibiotics;
- 6. Perform effective drainage of infected foci;
- 7. Avoid antibiotic damage to the organism’s ecosystem.
Antibiotics are widely used in intensive care units around the world. It is very important for patients with community-acquired sepsis or hospital-acquired sepsis to receive adequate and broad-spectrum anti-infective treatment early. However, the current status quo is that the anti-infection strategies for critically ill patients are not always targeted; and more than half of the patients cannot be clearly infected when they receive anti-infection treatment.
At present, most people believe that anti-infective de-escalation therapy affects the therapeutic effect. When ICU patients infected with multi-drug-resistant bacteria are transferred out, they will spread the bacteria to other parts of the hospital, causing the migration of multi-drug-resistant bacteria. In view of the serious consequences of antibiotic abuse, ICU doctors should pay attention to the selection of antibiotics throughout the treatment process, optimize the use of antibiotics, and avoid drug abuse.
3. Antibiotics and bacterial resistance
Beta-lactamase-producing Enterobacter (ESBL-E) and multi-drug resistant Pseudomonas aeruginosa are increasing, carbapenem-resistant Acinetobacter baumannii and carbapenemase-producing Enterobacter ( CRE) has spread globally, and methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci have brought serious consequences in many areas. What is certain is that the emergence of drug-resistant bacteria has seriously affected the treatment effect of patients and caused bad results.
Cross-sectional surveys show that up to 70% of ICU patients receive antibiotic treatment. The antibiotic exposure of ICU patients is three times that of general wards, and the level of antibiotic use is higher.
At the patient level, antibiotic exposure caused dysbiosis. Bacteria that are not affected by the antibiotics used in the body will grow. Therefore, single-drug use can cause the growth of some non-fermenting bacteria in the body and screen out resistant bacteria. At the ICU level, the excessive use of a certain drug without considering environmental factors and equipment can cause the proliferation of multi-drug resistant bacteria in the entire environment.
When fighting infections, in view of the local ecological effects of antibiotics, it is necessary to consider whether they have an anti-anaerobe effect. Sometimes, multi-drug-resistant gram-negative bacteria can be disturbed by anaerobic bacteria and lose their pathogenic ability. Therefore, anti-anaerobe treatment can cause ESBL-E and AmpC enterobacteria (Editor’s note: β-lactamase Ambler molecular structure classification method) Type C in C, acts on cephalosporins, is not inhibited by potassium clavulanate, and decomposes cefoxitin) and the flooding of CRE. The effect of anti-anaerobic drugs secreted by the biliary system on the organism’s ecology is different from that of the intestine.
4. Risk factors for multi-drug resistant bacteria
The clinical significance of identifying risk factors for multidrug-resistant bacterial infections (MDRB) is that a broad-spectrum anti-infective treatment can be performed before the culture results are available. The host, pathogenic bacteria, environment and other conditions are extremely complex, leading to the lack of effective means to identify whether patients are susceptible to infection with multi-drug resistant bacteria.
Therefore, when anti-infective treatment is performed, individualized selection is required. It can be judged from 6 sections (patient characteristics, infection type, antibiotic exposure history, bacterial rating, local epidemiology, medical environment) whether a patient has high-risk factors for MDRB infection, refer to the figure below for details.
The colonization of pathogenic bacteria greatly increases the risk factors for multi-drug-resistant bacteria infection, but it should be known that even if pathogenic bacteria are colonized, the probability of a patient being infected with multi-drug-resistant bacteria will never exceed 50%. For example, in cultured ESBL-E patients, only 10-25% consider this bacterial infection (Editor’s note: the cultured pathogen does not mean that the patient has an infection). Whether the carrier will have the corresponding infection depends on many aspects, such as immune function, disease state, etc. Therefore, even if the patient has a history of pathogen colonization, it is not necessary to choose broad-spectrum antibiotics when fighting infection.
Patients with more basic diseases, long hospital stays, invasive treatments such as deep vein puncture, and exposure to antibiotics increase the risk of MDRB infection .
The prevalence of MDRB varies from place to place, so when considering MDRB infection, it is necessary to refer to the specific local conditions. Even in different hospitals in the same city, the characteristics of pathogens are not necessarily the same, because different places have different economic levels, patient management intensity, and environmental conditions.
5. Conditions that do not require anti-infection
Regardless of the number of organ failures, for patients with sepsis or septic shock, the available evidence supports immediate anti-infective treatment. But currently diagnosing sepsis itself is quite challenging. According to the survey, up to 50% of fever patients are not caused by infection. At the same time, collecting pathogenic evidence is time-consuming and requires a long wait. If the patient receives antibiotics before the bacterial culture, the positive rate of culture will decrease, resulting in unreliable culture results.
Clinically, in patients considering infection, the negative rate of culture fluctuates between 30-80%. One-third of patients with severe pneumonia who need to be admitted to the ICU for treatment are viral infections, which leads to uncertainty in the initial antibacterial treatment.
In 2016, the sepsis 3.0 diagnostic criteria proposed the rapid SOFA score (qSOFA) to quickly diagnose sepsis at the bedside. Although this score has a certain effect, whether it can be used as an indicator of antibiotic use is still controversial. At the same time, studies have shown that the qSOFA score lacks sensitivity in the diagnosis of sepsis.
At present, antibiotics are widely used in ICU, but there have been studies showing that the use of antibiotics in large amounts is harmful. Starting antibiotic treatment after it is clear that there is an infection can reduce the case fatality rate by 50%. The benefits of this approach are consistent with the appropriate start of anti-infection treatment strategies and short-term anti-infection strategies.
Biomarkers can help diagnose infections and, to a greater extent, help clinicians rule out infections, thus reducing the use of unnecessary antibiotics, forcing clinicians to look for other diagnoses.
There are many markers found, but few practical ones. PCT will increase in patients with bacterial infection, but it will not increase in viral infections. In patients with systemic inflammatory response syndrome not caused by infection, PCT does not increase. However, current studies have shown that PCT-guided anti-infective treatment, such as guiding the course of anti-infective treatment, guiding the initiation of antibiotics, etc., does not improve the prognosis of patients and does not reduce the use of antibiotics. Therefore, PCT cannot be used alone to guide the application of antibiotics, especially the initiation of antibiotics. It should also be combined with the patient’s symptoms and signs, such as fever.
Clinical symptoms and signs combined with laboratory tests can help distinguish bacterial infections from non-bacterial infections. Multiple biomarkers can be used together to rule out sepsis. The current PCR technology for identifying microorganisms has high specificity, but lacks the corresponding sensitivity. Therefore, it will increase the diagnosis of infection.
In other words, at present, it is still difficult to diagnose infection clinically, and clinicians still need to determine when to use antibiotics and when to stop antibiotics based on their own experience.
6. Focus on host immunity
The host immune status is an important factor affecting the initiation of antibiotics. Patients undergoing organ transplantation may suffer from sepsis or septic shock. These patients may not have fever or elevated white blood cells because of immunosuppressive agents. The immunosuppressant taken by the patient depends on the type of organ transplantation, and the focus of infection may not be the same. The type of infection can be roughly inferred from the time of infection of organ transplant patients, whether it is a hospital infection or an opportunistic infection.
Patients undergoing chemotherapy will have immunosuppression and persistent neutropenia. These patients can use broad-spectrum anti-infection strategies. HIV patients are not only prone to community-acquired infections, but also opportunistic infections, depending on the patient’s CD4 cell count. Other immune states include immunoglobulin deficiency and iatrogenic immunosuppression. Patients with immune insufficiency have defects in a variety of immune pathways, so they can have co-infections, such as bacterial infections, viral infections, and fungal infections. What needs to know is that the immune status of elderly patients will also decline, which includes acquired immunity and innate immunity, making them more prone to infection.
7. Clarify the etiology
In the early stage of infection, because it is not known which type of bacteria the infection is, broad-spectrum anti-infection treatment can be used. After the etiology is clear, it is necessary to turn to targeted treatment, that is, de-escalation treatment. The time between broad-spectrum anti-infective treatment and targeted treatment can be called TAT (turnaround time). It takes at least 48 hours for traditional culture to obtain the etiology and drug sensitivity results. During this time, whether the anti-infection can cover the infectious flora has become an unknown.
Molecular diagnostic strategies are currently developing rapidly, which can shorten the time of pathogenic diagnosis and are no worse than traditional culture in terms of sensitivity and specificity.
At present, many methods for identifying pathogens have been developed based on PCR technology, and they can also provide some drug susceptibility information of pathogens, some of which have been successfully implemented clinically to diagnose appropriate infections (such as bloodstream infections, Pneumonia, meningitis), provides a new solution for bacteriological diagnosis.
The identification of pathogens by PCR technology is faster than traditional methods, and it only takes 1.5-6 hours. If conditions permit, even if the specimen is processed, the results can be obtained faster.
The PCR-derived treatment method is expensive, and it is recommended to be carried out together with traditional culture. The results of the two are compared to guide the clinic.
The current genetic technology has been able to identify bacterial gene expression, such as monitoring ESBL genes and carbapenemase genes, to diagnose whether the bacteria have corresponding drug resistance. More research is needed to clarify whether this technique can improve the prognosis of patients .
At present, the more popular is the clinical metagenomics technology, which pays attention to extracting nucleic acids from specimens and then performing whole-genome analysis, which can identify all pathogenic bacteria and their drug resistance. At present, Cambridge University can provide the corresponding technology. This method can also be used to assess host response. This technology is under research and cannot be applied clinically.
All inspection items for etiology must be combined, together with the patient’s imaging, symptoms, etc., to serve the clinic.
Pathogenic diagnosis method
8. Avoid underdose
Evaluation of the optimal dose of antibiotics needs to consider the MIC and the site of infection. Unfortunately, there is still a lack of clear guidance on how to adjust the dose of antibiotics based on the MIC and the site of infection, resulting in uncertainty about the efficacy of anti-infection.
For sepsis patients with negative culture results, it is more difficult to determine the drug dose. In this case, it is a reasonable approach to make the antibiotic concentration used reach the highest MIC level of the potential pathogen.
It is important to know that in ICU patients, underdose of antibiotics is very common.
According to the survey, for those patients receiving β-lactam drug therapy, up to one-sixth of the patients failed to meet the minimum drug concentration requirement (this requirement refers to the need to ensure that during the interval between β-lactam drug administration, 50% % Of the time, the drug concentration is higher than the MIC), and more patients’ drug concentration fails to reach the maximum bactericidal concentration (during the entire dosing interval, the drug concentration is greater than 4 times the MIC value).
The first hour of anti-infective treatment is very important, but considering that the clinical drug concentration is rarely up to standard, the anti-infective effect is very worrying. Unfortunately, there is currently no standard treatment method for this problem. In the process of medication, it is necessary to consider the physical and chemical properties of the drug (such as hydrophilicity and lipophilicity), the patient’s own condition, clinical implementation, and organ function support (such as kidney Replacement therapy or extracorporeal membrane oxygenation).
The volume of distribution is an important determinant of the effective antibiotic concentration, but it cannot be measured in ICU patients. For patients with evidence of increased volume of distribution (such as positive fluid balance), especially when using hydrophilic antibiotics, whether it is intermittent or continuous administration, a larger load should be given to ensure that the drug can be quickly Achieve sufficient and required tissue concentration.
For antibiotics that are mainly metabolized by the kidney or only metabolized by the kidney, the patient’s renal function can be ignored when the first dose is administered.
In the ICU, many antibiotics are metabolized by the kidneys. For patients with acute kidney injury or increased renal clearance (measured creatinine clearance ≥130 mL/min/1.73 m2), dosage adjustments should be considered.
Patients with increased creatinine clearance will cause increased drug clearance, which will lead to insufficient drug concentration, which means that higher drug doses are required to reach the target blood drug concentration, but in this case, blood drug concentration needs to be monitored to avoid drug overdose . The use of antibiotics can be optimized by pharmacokinetics (PK)/pharmacodynamics (PD). There are already some independent drug monitoring software, but these software still need to be integrated into the drug monitoring system to further guide the use of antibiotics.
9. Drug concentration monitoring
Antibiotics are time-dependent and concentration-dependent. For the time-dependent, the longer the antibiotic concentration exceeds the MIC, the better the effect; for the concentration-dependent, the more the concentration exceeds the MIC, the better the effect.
Drug dose monitoring can reduce the amount of drugs used, avoid toxic side effects, and at the same time ensure that the drugs reach the effective concentration and exert sufficient anti-infective effects.
For aminoglycoside drugs and glycopeptide drugs, concentration monitoring is more important. When using aminoglycoside drugs, it is beneficial to maintain a higher peak concentration for patients with severe multi-drug resistant bacteria infections and ventilator-associated pneumonia. For vancomycin, when it is used to treat bloodstream MRSA infections, a sufficient trough concentration can improve the prognosis of patients. When using vancomycin, it is necessary to monitor the trough concentration. If the patient’s renal function is good and the creatinine clearance rate is increased, the appropriate trough concentration cannot be reached under the conventional dosage.
For β-lactam drugs, whether drug concentration monitoring can bring benefits is controversial.
- First, this type of drug concentration monitoring lacks effective and reliable means;
- second, blood drug concentration monitoring takes time, and for most hospitals, the monitoring results cannot be obtained in time;
- third, there are many problems with sample sampling;
- fourth At present, only retrospective studies have shown that insufficient doses of β-lactam drugs can affect the prognosis, and the level of evidence in the research is not high;
- fifth, there is no evidence to prove that sufficient amounts of β-lactam drugs can improve patients with multi-drug resistant bacteria infections. Prognosis.
- Sixth, β-lactam drugs are time-dependent. It is difficult to monitor the time when the drug concentration is above the MIC, and it is difficult to determine the time when the drug exceeds the MIC.
- Seventh, it takes time to obtain MIC, leading to a serious lag in drug concentration monitoring.
In view of the above reasons, for β-lactam drugs, epidemiological thresholds can be used to define the drug concentration, but currently few hospitals can monitor the corresponding drug concentration. Higher concentrations of β-lactam drugs may cause toxic and side effects, which is also a problem that needs to be considered when monitoring the concentration of such drugs.
Therefore, for time-dependent antibiotics, blood concentration monitoring is very promising, and judges can design trials for clinical research.
10. New antibiotic
Polymyxin is considered to be the cornerstone of the treatment of pan-resistant bacterial infections, including the treatment of carbapenem-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Studies in recent years have confirmed that polymyxin is not as severe as nephrotoxicity and neurotoxicity as previously reported. In response to pan-drug resistant bacteria infections, there are currently controversies about whether to combine drugs, the best dose, and how to prevent the emergence of resistant bacteria. Polymyxin has a certain status for this infection.
There are currently some drugs under research, such as ceftazidime and avibactam, ceftazidime and avibactam, aztreonam and avibactam, carbapenem combined with new enzyme inhibitors, Cefadil, sisomicin, iravacycline, etc. These drugs are mainly performed on complicated urinary tract infections, abdominal cavity infections, skin and soft tissue infections, and there is a lack of relevant information in ICU patients. Studies have shown that ceftazidime and avibactam are very effective in the treatment of some CRE bloodstream infections.
For positive bacterial infections, in addition to glycopeptide drugs, there are currently daptomycin (treatment of bloodstream infection) and linezolid (treatment of HAP) can be used. These alternative medicines can be used in patients with a higher risk of acute kidney injury. Daptomycin is safe even in large doses and long-term use. Rhabdomyolysis is rare and some side effects are reversible. In contrast, linezolid has some risks, especially in patients with kidney injury and blood system disease.
The long-term use risk increases, so it is necessary to monitor the drug concentration. Next-generation cephalosporins such as ceftaroline and cefdilor can also be used to treat MRSA infections, even in the elderly. There are also some other new drugs, such as lipoglycopeptide drugs (dalbavancin, oritavancin, tiravancin), fluoroquinolones (delafoxacin, neroxacin, zabofoxacin), oxazolidinones (Tedizolamide), dihydrofolate reductase inhibitors (alaprin) and tetracycline drugs (Omacycline) can be used to treat MRSA, but further clinical studies are needed to confirm their efficacy.
11. Medication alone or in combination
Compared with the single use of broad-spectrum antibiotics, the combination of antibiotics can improve the prognosis, which is controversial. Meta-analysis found that β-lactam drugs used alone or in combination with other drugs have no advantage in the treatment of a series of Gram-negative bacterial infections, but it is important to know that this study did not include sepsis or Patients with septic shock. On the contrary, another meta-analysis found that for patients with sepsis or septic shock (high-risk patients, such as the expected mortality rate> 25%), the combination of drugs is beneficial. In the case of neutropenia or the possibility of pathogen resistance This principle can be used especially when it is higher (such as Pseudomonas aeruginosa).
There are no clinical trials that can confirm that the combination of drugs is better than the single drugs in the treatment of carbapenem-resistant enterobacteria. Observational studies suggest that for critically ill patients (septic shock) or patients with more complications, combined medication has certain benefits. At present, it is difficult to determine the best anti-infection plan; only one article found that the combination of three drugs (polymyxin, tigecycline, meropenem) can improve survival.
At present, there are five RCT studies and several meta-analysis for carbapenem-resistant Acinetobacter baumannii, but none of them can clarify the best anti-infective treatment strategy. These RCT studies can not confirm that the combination of drugs can improve the survival rate; but one study shows that polymyxin combined with high-dose ampicillin and sulbactam can have a better clinical outcome. Three studies have found that when polymyxin is used in combination with rifampicin or fosfomycin, the bacteria are eliminated faster. But a recent meta-analysis found that polymyxin combined with other drugs can improve survival when treating bacteremia.
12. Intermittent or continuous infusion
For time-dependent antibiotics (such as β-lactam drugs), the time when the drug concentration exceeds the MIC during the intermittent period of administration can predict the anti-infective effect. This effect can be achieved by reducing the dosing interval or extending the infusion time, such as continuous infusion administration or 3-4 hours per administration. According to research, extending the infusion time of β-lactam drugs can increase the probability of drug concentration exceeding MIC.
Most RCT studies have failed to find that when β-lactam drugs are used, intermittent administration or prolonged infusion time can improve the prognosis. However, a recent meta-analysis found that in patients with sepsis, the use of anti-pseudomonas β-lactam antibiotics, continuous infusion compared to intermittent administration, can improve the prognosis. Extending the infusion time may be suitable for these patients: 1. Intermittent infusion cannot achieve satisfactory blood drug concentration (drug dose is insufficient); 2. Pathogen MIC is too high. Currently conceivable, if the patient is septic, and is the need to use an anti-Pseudomonas β-lactam antibiotics, infusion can be extended between.
For vancomycin, AUC/MIC is an index to evaluate its efficacy. Current studies have shown that continuous infusion of vancomycin can reduce nephrotoxicity, but it does not reduce the mortality rate and improve the prognosis. Moreover, this study has many flaws, which need to be further confirmed in the future.
13. De-escalation therapy
When the anti-infection has been effective, you can try de-escalation therapy to reduce exposure to broad-spectrum antibiotics and avoid bacterial resistance. This means that after the bacterial susceptibility results come out, the effect of antibiotics needs to be reassessed. But at present, there is still a lack of clear and consistent concepts about de-escalation therapy, so that it is clinically ambiguous. When the pathogenic bacteria are clear, the step-down requirements 1. Change to narrow-spectrum antibiotics; 2. Choose antibiotics that have less impact on the organism’s microecology; 3. Stop the combination medication.
According to surveys, in clinical practice, only 40-50% of patients with bacterial infections will receive de-escalation therapy. This reflects that clinicians are not willing to switch to narrow-spectrum antibiotics when faced with culture-negative sepsis or MDRB infection. But you need to know that there is currently no evidence that de-escalation therapy can bring adverse effects, even if the patient has many high-risk factors (bloodstream infection, severe sepsis, VAP, neutropenia). Of course, a well-designed RCT test is needed in the future to confirm the effectiveness of the downgrade.
At present, more and more doctors are beginning to recognize and gradually implement de-escalation treatment programs. Unfortunately, there is currently a lack of evidence that de-escalation therapy can reduce the use of antibiotics and reduce the rate of resistance. In fact, de-escalation therapy can reduce the use of one class of antibiotics, but it does not reduce the use of antibiotics throughout the course of the disease. Some studies have even found that de-escalation therapy can increase the use of antibiotics. Several RCT trials have shown that de-escalation therapy has little effect on mortality and can hardly prevent the production of resistant bacteria.
In view of the above analysis, the use of antibiotics should be closely monitored clinically to reduce adverse drug reactions, and the latest technology should be boldly used to clarify the etiology as soon as possible and obtain drug susceptibility results as soon as possible. In the future, big data is needed to confirm the impact of step-down treatment on the entire ecological environment and further support the step-down treatment plan.
14. Antibiotic course and resistance
Long-term use of antibiotics can cause bacterial resistance. Studies have shown that short-term antibiotic therapy is effective and safe for community-acquired pneumonia, VAP, urinary tract infection, bacteremia, etc. Even in patients with sepsis, it is safe to shorten the time limit of antibiotics based on PCT. Unfortunately, the ProACT study shows that for patients with lower respiratory tract infections, using PCT to guide antibiotic treatment time, compared with other indicators, cannot shorten the antibiotic exposure time. And PCT examination will increase the financial burden of patients.
Many institutions and guidelines encourage doctors to shorten the use of antibiotics during treatment. For pneumonia, urinary tract infections, etc., short-term antibiotic therapy can be used. Despite this, the current situation of excessive use of antibiotics is still very common. Of course, clinicians need to be clear that short-term antibiotic therapy is not recommended when patients have long-term neutropenia, insufficient drainage, multi-drug resistant bacteria infections, vascular or prosthetic infections.
The treatment of infected lesions is very important, even more important than adequate early antibiotics. For infection, surgical or interventional methods must be considered to effectively treat the infection.
The drainage of the infected foci is time-dependent. For patients with septic shock, the earlier the treatment of the infected foci, the better the outcome. For some mild patients, the treatment time of the infected foci can be appropriately delayed under close monitoring. Patients whose infection foci cannot be treated in time, even after receiving adequate fluid resuscitation and anti-infection treatment, will experience persistent or new organ dysfunction. What needs to be clarified is that when the infected foci are processed, specimens should be submitted for examination as much as possible in order to obtain drug susceptibility results of pathogenic bacteria as soon as possible and facilitate effective anti-infective treatment.
16. Antibiotic management procedures
The use of antibiotic management procedures (ASP) in the ICU can improve the utilization of antibiotics, reduce the use of broad-spectrum antibiotics, reduce the incidence of infection, avoid the production of multi-drug resistant bacteria, and reduce the side effects of antibiotic use, which has many benefits. ESCMID research shows that antibiotic management procedures require a series of measures to ensure that the use of antibiotics is sufficient and effective. This set of procedures requires that in the ICU, there is an experienced doctor to check the use of antibiotics. Each ICU should establish and gradually operate its own antibiotic management program (ASP) based on its own conditions.
17. Antibiotic use panel
The continuous update of patient and other information is very important for clinicians. Multi-drug resistant bacteria will continue to mutate, so monitoring the resistance of the bacteria in the local area will help the use of broad-spectrum antibiotics. At present, technology is advancing rapidly, and clinicians can obtain relevant patient information in a timely manner through a series of analysis software, which can be displayed on the electronic panel. These panels should show the patient’s resistance to pathogenic bacteria, the use of antibiotics, and the patient’s infection (focus, type, severity), etc. At present, some people have gone to study that this panel can improve patient prognosis, but it is clear that it can help clinicians to a large extent.
The poor treatment effect of bacterial sepsis and the severe situation of multi-drug resistant bacteria all urgently need to strengthen antibiotic management. In the process of using antibiotics, we need to think about: 1. Whether the rapid diagnostic tool is effective; 2. Single drug or combination drug; 3. How to control the drug dosage; 4. How to formulate antibiotic management procedures. In the future, more effort should be spent on controlling the prevalence of multi-drug resistant bacteria.
(source:internet, reference only)