Pay attention to the detection, prevention and treatment of "super bacteria"

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Pay attention to the detection, prevention and treatment of "super bacteria"Interpretation and Reflection on the "super bacteria guide" in t


Pay attention to the detection, prevention and treatment of "super bacteria"

Interpretation and Reflection on the "super bacteria guide" in the UK National Health Service (NHS)

Shi y

Department of respiration, Nanjing General Hospital of Nanjing military command, Beijing 210002, China

[Abstract] the "super bacteria" refers to the effective treatment of almost all resistant bacteria, including carbapenem resistant gram negative bacilli is the main problem in recent years the clinical encounter, the irrational use of antimicrobial drugs and make clinical treatment more difficult. Therefore, it is necessary to strengthen the detection and monitoring of the enzyme, to prevent the production and dissemination of the production and the use of antibiotics. It is very important to participate in the management of medical institutions, laboratory quality control, the use of antibiotics, and control of hospital infection.

Key words: beta lactamase; carbapenems; drug resistance; prevention; treatment

CareonDetection, PreventionandTreatmentofSuperbugs

Theterm "superbugs" referstomicrobeswithresistancetoalmostallantibioticsspecificallyrecommendedforthetreatment.

KeyWords: -lactamases; Carbapenemase; Drug-resistance; Prevention; Treatment


Departmentofrespiratorydiseases, Nanjinggeneralhospitalofnanjingmilitarycommand, Nanjing210002, Jiangsu, China

Bacterial resistance caused by "super bacteria (superbugs)" has become a global hot issue, not only is the medical attention, the general public is also very concerned about. The emergence of type I metallo beta lactamase (NewDelhiMetallo- beta -Lactamase, NDM-1) in New Delhi once again sounded the alarm for us. As we know, carbapenems (imipenem, meropenem, panipenem, biapenem, doripenem and ertapenem) antibiotics in multidrug resistance (including producing ESBLs, ESBL) treatment of gram-negative bacilli infection and achieved satisfactory effect, but with the wide use of broad-spectrum antibiotics. Especially unreasonable application, has begun to appear carbapenem resistant Enterobacteriaceae, although the number is not much but we have found a new type of resistance, propagation characteristics and pathogenesis of the latter is similar to other sensitive Enterobacteriaceae, it is very difficult but once patients infected after treatment. Based on the above reasons, the British national health service system (NHS) developed the "guidelines of carbapenem resistant enzyme producing bacteria (Guidanceoncarbapenemresistanceproducers) (hereinafter referred to as the guide) [1] - for carbapenemase producing bacteria advice: understanding, infection control and treatment, put forward the corresponding detection method, some the value of preventive measures and effective drug treatment, is a good guidance for domestic clinical practice, combining with my own understanding and experience introduction as follows.

First, the understanding of "super bacteria"

The so-called "super bacteria" is not a new term, found that in 2005 the United States statistics by methicillin resistant Staphylococcus aureus (MRSA) infection causes mortality than AIDS when they put forward the concept, it is a pity that this warning does not cause people's attention, multi drug resistant bacterial growing. The name "super bacteria" is not a specific bacteria, bacteria in general but a class to almost all antibiotics have significant resistance, including MRSA, vancomycin resistant enterococci (VRE), vancomycin resistant Staphylococcus aureus (VRSA) and carbapenem resistant gram negative bacilli. Carbapenem antibiotics as an important drug in the treatment of gram negative bacilli producing ESBLs, the resistance rate increased with the increase of the use rate. Therefore, the production of carbapenemase bacteria have the ability to become the "super bacteria of the family, the bright younger generation" the momentum of development without any signs of slowing. Moreover, compared with gram positive bacteria, the development of new drugs against gram negative bacteria should be significantly delayed. The British guidelines are mainly for the diagnosis and treatment of multidrug-resistant gram negative bacteria, in particular for the production of carbapenem Enterobacteriaceae infections [1].

Enterobacteriaceae in carbapenem resistant bacteria include the following two categories: the extended spectrum beta lactamases (ESBL) or producing AmpC enzyme and accompanied by membrane protein deficiency: bacterial porin loss is usually not stable, increase its resistance value is limited, suggesting that these strains rarely spread. Ertapenem are particularly susceptible to this resistance mechanism. Acquired carbapenem bacteria: the risk of this type of bacteria is greater, and is to have a variety of antibiotic resistant Enterobacteriaceae bacteria. They have three types: one is the metal enzyme molecules such as IMP, VIM, NDM, the active site has zinc ion; two are independent non metal enzyme family such as KPC and OXA-48; three other carbapenemase producing bacteria such as SME, IMI and SPM, but rare (see Table 1). The antibiotic resistance monitoring and reference laboratory (ARMRL) data show that the annual output of 2010 tons of carbapenemase number of bacteria compared to 2003 increased by nearly 300 times (see Figure 1), among which the most common KPC (2/3), followed by NDM, VIM and OXA-48, while IMP is rare [2,3,4]. China situation is not optimistic, 2005-2010 CHINET confirmed that China's drug resistance monitoring data of bacterial resistance and environment of the world and is a growing trend, the drug resistance of Klebsiella pneumoniae to carbopenems rate also increased significantly (Figure 3) [5], so we never paralysis.

Table 1 main types of carbapenems: distribution and molecular epidemiology

geographical distribution

molecular epidemiology


Widely spread in Enterobacteriaceae (especially Klebsiella pneumoniae and Escherichia coli in India and Pakistan).

Patients in India and Pakistan enter the UK by travel / hospital / dialysis.

There are many strains in britain.

Plasmid mediated resistance spread between different bacteria and strains is more important than clonal spread among patients.

There are a few cases of cross infection in the uk.


Scattered throughout the world, popular in Greece; mostly Klebsiella pneumoniae. It is sometimes imported into the UK by a patient who was hospitalized in greece.

The spread of plasmids between different strains was more important than the clonal spread among strains.


There was no significant correlation between the distribution of global dispersion.

Mainly through plasmid transmission.


From the United States in 1999, popular in Israel, Greece, in other European countries outbreak. Some British cases are imported by patient travel, but endemic in northwestern England.

Some of them are spread by plasmid: most of them are transmitted from Klebsiella pneumoniae to other enterobacteriaceae. It can also be transmitted through cloning, including the spread of Klebsiella pneumoniae in the world ST258.


The spread of Klebsiella pneumoniae in Turkey, the Middle East and North africa. Some strains were imported into the UK, and in September 2008 there was an outbreak of a kidney disease in london.

Plasmid transmission and clonal propagation.

Figure 1. Data on the production of carbapenems from ARMRL


Antibiotic resistance monitoring and reference laboratory

Figure 2 the resistance rate of Klebsiella pneumoniae to carbapenems

(2005-2010 China CHINET resistance monitoring data)

In two, the production of Penicillium sp.

To understand the epidemic situation of producing carbapenemase bacteria, must have a reliable method to detect carbapenemase, but even in a special laboratory standard of British standard method is still in discussion, many influence factors. For the first time, the sensitivity of carbapenem producing Enterobacteriaceae to carbapenem antibiotics may be only slightly reduced, which requires the laboratory to have a higher sensitivity to detect edge strains. Secondly, most enzyme producing bacteria is mainly to beta lactam antibiotics, but the enzyme producing bacteria carrying OXA-48 gene may still sensitive to cephalosporins, this automatic detection system used in drug sensitivity when there may be a problem. This suggests that the higher requirements of detection of carbapenemase, while China has ability to do this testing in laboratory is not much, should strengthen the construction and standardization, and to those who wish to carry out this test laboratory physician specialized training, to ensure the quality of detection. The government should establish the reference to the British as the laboratory base, assistance to the country to carry out detection of carbapenemases, content should include: confirmation of antibacterial spectrum; type II identification of carbapenemase; confirm the outbreak of the epidemic of drug-resistant strains; tracking spread of resistant strains of cloning [6,7].

Not all gram negative bacteria need to be detected in clinical practice, and the UK guidelines are available for our reference. They consider the following situations without investigation: Proteus only resistant to imipenem, low sensitivity of these bacteria has inherent; II to cephalosporins and low levels of resistant but ertapenem to imipenem and meropenem sensitive Enterobacter bacteria, these bacteria are also produced AmpC enzymes and membrane permeability decreased. Acinetobacter and Pseudomonas aeruginosa were resistant to carbapenems, unless these bacteria have high levels of resistance (such as in carbapenems culture medium) or ethylenediaminetetraacetic acid (EDTA) - imipenem synergy test positive, suggesting that the presence of metal enzyme. These proposals are suitable for our country situation, still need our own data to prove [7,8,].

At present, the detection methods of carbapenems have "Hodge" test (see Figure 3) and collaborative test (Figure 4), but these methods have no clear interpretation of the standard, it is for reference only.

Figure 3 "Hodge" test figure 4 collaborative test

1 "Hodge" (alfalfa, Cloverleaf) test (Figure 3): the Escherichia coli NCTC10418 (or ATCC25922) with agar plate for drug susceptibility test; the 3 arm form 120 degrees equally will cut into the tested strains or the formation of deep stripe from flat to central inoculated agar 3; containing imipenem, meropenem and ertapenem each 10ug pieces were placed in the end of the 3 arm; the bacteriostatic ring depression shows that the antagonistic strains of carbapenem antibiotics. It should be noted that the reading of the results is influenced by subjective factors, and the AmpC enzyme can be expressed as a result of a weak false positive.

2 synergy test (Figure 4): metal carbapenemase (IMP, NDM, VIM) can be EDTA or two 2,6- pyridine carboxylic acid inhibitor; synergistic effect between the carbapenems and EDTA suggests the presence of metallo beta lactamase (MBL), Etests or by double disk test; third note Italy of Pseudomonas aeruginosa and Acinetobacter Bauman often false positive results, but rare in enterobacteriaceae. KPC enzyme by boric acid inhibited the synergistic effect of boric acid and imipenem double disk disk suggests the presence of KPC.

Three. Measures to reduce the risk of carbapenems

The most effective way to eliminate the enzyme producing bacteria is to prevent the occurrence of drug resistance, including antibiotic management, infection control and rational use of antibiotics. The current situation of our country is often treated with light prevention, even if the preventive measures are abstract and lack of maneuverability. The UK guide lists a number of specific preventive measures, such as the involvement and support of leadership and management, and specific infection control measures, which are worth learning from (see Table 2) [9,10].

Antibacterial drug management is an important measure to reduce the drug resistance of bacteria, which is China's one of the missing items, even if the rules are often non-existent, it is difficult to implement. The UK guidelines recommend the adoption of a multidisciplinary team to ensure the implementation of various management measures to promote the rational and safe use of antimicrobial drugs to reduce the occurrence and spread of drug resistance. Recently, China's Ministry of health will soon introduce a "antimicrobial management approach", will have a profound impact on the rational use of antibiotics in china.

Endoscopy has become an important means of clinical diagnosis and treatment, with particular emphasis on the British guide endoscopic operation on the effects of infection, because of known endoscopy and related procedures can lead to the spread of drug resistant pathogens, such as the UK and France have several endoscopic correlation of carbapenem resistant strains spread reports. Therefore, our country should education related staff know these risks and take careful procedures, should also pay particular attention to disinfection or protection and endoscopic used together with other devices such as cameras, which are not usually routine disinfection [10,11].

Table 2 measures to prevent the dilution of Penicillium sp.

Standard practice measures

Case number

Participation of medical institutions


> 1

L ensure that leadership and management are highly motivated to reduce the spread of low - carbon Penicillium - enzyme bacteria, and support all the prevention and removal measures.




L to develop action plans (all medical institutions need to develop).



L optimization and summary of laboratory methods for enzyme production.




L with MacConkey or CLED or meropenem ertapenem agar medium inoculated with feces and rectal swabs and other parts (such as swabs from skin wound / catheter site) were cultured to screening of pathogens. Check the number of colonies in the corresponding area. The preferred nutrient rich broth may be useful: medium rectal swabs were inoculated with 5-10ml broth containing 10ug to imipenem on line training.



Infection prevention and control

L identify effective isolation areas, such as Suites / social areas, to develop standards for ward closure and reopening.


L establish effective disinfection measures. If it can not be effectively disinfected, the use of special or disposable equipment.


L immediately take precautions against the standard and infection control precautions and isolate the patient in a separate room with a bathroom or toilet.



L optimization of comprehensive care and clinical application of indwelling devices.




L wash hands frequently with soap to ensure hand hygiene.



L screening of all indications and secondary contact cases: timely detection and isolation of cases, clear spread of the situation, do a good job of the patient's mark.



The l was screened at the time of discharge in the affected area / ward until the pathogen was removed. There is no strong evidence to support screening. The urine was found in some continuous carrier carrying bacteria were not shit. Isolation of family members of patients is still controversial, but can be considered for implementation.



L do effective reinforcement and end cleaning in high exposure areas and public places to reduce spread (consider increasing frequency and use of disinfectants).



L hire more people based on risk assessment.



L summarize the effective measures of instrument disinfection.



L if the spread occurs, track the progress of events, draw epidemiological charts.



L prepare for readmission and transfer of infected patients.



L ensure adequate communication with other health workers.



Hospital scope

L raise awareness of medical staff, held training activities.




L screening in patients with high risk factors, such as positive culture, had been in the country where the prevalence of enzyme production in patients with diabetes or blood purification.




L if a transmission is detected, a panel meeting shall be held regularly to summarize the measures of infection prevention and control, and to analyze the root cause.



L high risk patients in the classification / admission device isolation strategy.


L device communication strategy.


L ensure that any communication will be the first priority for healthcare organizations (from the committee to the district leadership).


Four, the treatment of bacterial infection caused by carbapenem

Most of the carbapenem producing bacteria are highly resistant to the drugs. China's Ministry of health on 2010 issued the "guidelines for the diagnosis and treatment of NDM-1 producing Enterobacteriaceae infection (trial version)", recommended tigecycline, polymyxin, carbapenems, aminoglycosides, fluoroquinolones and fosfomycin and other 6 drugs in treatment of NDM-1 producing bacteria caused by infection, and developed a mild to moderate and severe infection in the treatment of patients, but is reasonable still need to carry on the clinical practice test. For example, aminoglycosides and fluoroquinolones are usually resistant to NDM, while in China the guidelines as recommended drugs, but this is very simple, the operability is not strong. Drug treatment guidelines for British recommended in detail, including the advantages and limitations, and the drug is usually not sensitive under the specific conditions were given trial indications of [12,13,14], and can be used as reference for our treatment, as follows.

1 beta lactam: usually bacteria for such drugs are resistant, but some drugs can be considered: the trial of aztreonam for metal carbapenemase (including IMP, VIM and NDM) is stable, but most of the enzyme producing bacteria also produced AmpC or ESBL resistance; aztreonam in gold genus of carbapenems such as OXA-48 and KPC are not stable. The ceftazidime, cefotaxime and aztreonam for producing OXA-48 but not AmpC or ESBL producing Enterobacteriaceae are still active; the TEMOCILLIN: the activity of KPC is relatively stable, but most of the MIC value slightly exceeds the allowable range of doses (2G, q12h); enzyme inhibitor and beta. At present, all of the drugs are not inactivated carbapenemase; the carbapenem: for some low level (< 4mg/l) enzyme producing bacteria resistance still active.

2 aminoglycoside: usually bacteria of such drugs are resistant: NDM-1 producing strains: usually contain 16S-rRNA methyltransferase, which bacteria are resistant to current clinical use of aminoglycosides; the KPC producing Klebsiella Lei Bojun (ST258): the most sensitive to gentamycin, but not sensitive to other aminoglycosides; the production of KPC, VIM, IMP and OXA-48 strains with multiple function modification enzymes on the aminoglycoside resistance varies greatly. Isepamicin effective for some isolates, although these strains of other aminoglycoside resistance.

3 colistin, tigecycline, fosfomycin: drugs in vitro most effectively, but there are limitations. The dosage should be adjusted according to the difference of the patient and the location of infection, and follow the principle of "the highest safety", not "the least possible".

Refer to table 3 for specific drugs recommended by the UK guidelines.

Table 3 drugs for the treatment of carbapenem producing strains




Polymyxin B and E (colistin)

(vein application)

For more than 90% of the production of carbapenems enzyme activity.

Successful treatment of a large number of carbapenem producing bacterial infections: a case report.

Obvious kidney and neurotoxicity; low permeability of lung tissue.

Pneumonia patients need high dose, may also need to add colistin inhalation atomization


(vein application)

In vitro, most of the carbapenem resistant Escherichia coli.

Approved for skin, soft tissue and complex abdominal infection.

Successful treatment of various infections caused by carbapenem producing bacteria.

Blood drug concentration is low; caution should be used for drug labeling; since only 22% of the kidneys are excreted, they are not suitable for urinary tract infections.

Increased mortality in some trials, such as mortality associated with ventilator associated pneumonia (unapproved indications).

Many Klebsiella are only 2mg/L (MIC), and some are resistant to antibiotics.


(oral and intravenous application)

The activity of most of the carbapenem producing Escherichia coli, including the production of NDM-1 strain.

Urinary tract infection.

Susceptibility to the critical state of Klebsiella is common.

Risk of mutation resistance.

The United Kingdom is not listed, but pharmacists can import drugs.

Other: a small number of isolates were sensitive to other antibiotics, such as chloramphenicol, ciprofloxacin and sulfamethoxazole. But most of the enzyme producing strains are resistant to these drugs.


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