Focus on detection, prevention and treatment of ‘superbugs’
–NHS Guidelines on Superbugs
Abstract
“Superbugs” are bacteria that are resistant to almost all effective therapeutic drugs, among which carbapenem-resistant Gram-negative bacilli are the main clinical problems in recent years. Therefore, the detection and monitoring of carbapenemases should be strengthened to prevent the production and dissemination of carbapenemase-producing bacteria and the correct use of antibiotic therapy. Very important among them is the involvement of the management of medical institutions, the quality control of laboratories, the standardized use of antimicrobial drugs, and the control of hospital infections.
【Key words】 β-lactamase; carbapenemase; drug resistance; prevention; treatment
Bacterial drug resistance caused by “superbugs” has become a global hot issue, which is of great concern not only to the medical profession but also to the general public. The emergence of New Delhi Metallo-beta-Lactamase (NDM-1) has once again sounded an alarm to us that it is urgent to deal with and solve the problem of bacterial drug resistance. We know that carbapenems (imipenem, meropenem, panipenem, biapenem, doripenem, and ertapenem) have achieved satisfactory efficacy in the treatment of multi-drug resistant (including ultra broad-spectrum β-lactamase-producing, ESBL) Gram-negative bacilli infections, but with the widespread and especially irrational use of these broad-spectrum antibiotics, carbapenem-resistant Enterobacteriaceae have begun to emerge. The latter have similar transmission characteristics and pathogenesis to other sensitive Enterobacteriaceae, but are very difficult to treat once patients are infected. For these reasons, the NHS has developed the Guidance on carbapenem-resistant producers (hereafter referred to as the UK Guidance) – which addresses The Guidance on carbapenemase-producing bacteria: awareness, infection control and treatment, proposes corresponding detection methods, some valuable prevention and control measures and potentially effective therapeutic drugs, which are of good guidance for domestic clinical practice, and are presented below with our own understanding and experience.
I. Understanding “superbug”
The so-called “superbug” is not a new term, as early as 2005 in the United States statistics found by methicillin-resistant Staphylococcus aureus (MRSA) infection caused by the rate of death than AIDS when the concept was proposed, but unfortunately this warning did not attract widespread attention, multi-drug-resistant bacteria continue to increase. Secondly, “superbugs” is not a specific name for bacteria, but a general term for a group of bacteria that are significantly resistant to almost all antibiotics, including MRSA, vancomycin-resistant enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA), and carbapenem-resistant gram-negative bacilli. . The resistance rate of carbapenem antibiotics, which are important drugs for the treatment of ESBLs-producing gram-negative bacilli, is increasing with the rate of usage. Therefore, these carbapenemase-producing bacteria have the ability to become the rising stars of the “superbug” family, and their development shows no signs of stopping or slowing down. Moreover, the development of new drugs for Gram-negative bacteria is lagging significantly behind that of Gram-positive bacteria. The UK guidelines provide advice on the management of multi-drug resistant Gram-negative bacteria, particularly carbapenemase-producing Enterobacteriaceae.
Carbapenem-resistant bacteria in the Enterobacteriaceae family include the following two major groups: (1) ultra broad-spectrum β-lactamase (ESBL) or AmpC enzyme-producing bacteria with concomitant membrane pore protein deficiency: membrane pore protein deficiency is usually unstable and has limited value in increasing resistance, suggesting that these strains are rarely transmitted. Ertapenem is particularly susceptible to this resistance mechanism. ②Acquired carbapenemase-producing bacteria: This type of bacteria is at greater risk and is spreading to Enterobacteriaceae that are already resistant to multiple antibiotics. They are of three molecular types: first, metalloenzymes such as IMP, VIM, and NDM, all of which have zinc ions in their active sites; second, a separate family of non-metalloenzymes such as KPC and OXA-48; and third, other carbapenemase-producing bacteria such as SME, IMI, and SPM, but rare (see Table 1). Data from the Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL) in the UK showed that the number of carbapenemase-producing bacteria increased nearly 300-fold in 2010 compared to 2003, with KPC being the most common (accounting for 2/3), followed by NDM, VIM and OXA-48, while IMP was less common. The situation in China is also not optimistic, the 2005-2010 CHINET drug resistance surveillance data confirm that China’s bacterial resistance and the world environment is no different and growing trend, in which Klebsiella pneumoniae resistance rate to carbapenems is also increasing significantly. We must not be paralyzed.
It is widely spread among Enterobacteriaceae (especially Klebsiella pneumoniae and Escherichia coli in India and Pakistan).
Patients from India and Pakistan import them into the UK through travel/hospitalization/dialysis.
Multi-type strains are available in the UK. , and
Plasmid-mediated resistance transmission between different bacteria and strains is more important than clonal transmission between patients.
There have been a few cases of cross-infection in the UK.
VIM
Globally scattered, with an epidemic in Greece; mostly Klebsiella pneumoniae. It is sometimes imported into the UK through patients previously hospitalized in Greece.
Plasmid transmission between strains is more important than clonal transmission between strains.
IMP
Globally scattered distribution, no significant correlation.
Primarily transmitted by plasmids.
KPC
Started in the USA in 1999, with epidemics in Israel, Greece and outbreaks in other European countries. Some UK cases imported by patient travel, but localized epidemic in NW England.
Partly by plasmid transmission: mostly between Klebsiella pneumoniae, occasionally to other Enterobacteriaceae. Also transmitted by clones, including Klebsiella pneumoniae ST258, which is globally transmitted.
OXA-48
Klebsiella pneumoniae is widely spread in Turkey, the Middle East and North Africa. Certain strains have been imported into the UK, and there was an outbreak in a nephrology unit in London in September 2008.
Both plasmid- and clonal-transmission have occurred.
II. Detection of carbapenemase-producing bacteria
To understand the prevalence of carbapenemase-producing bacteria, reliable methods for carbapenemase detection must be available, but even in the UK, where there is a dedicated standard laboratory, the standard methods are still being explored and there are many factors affecting them. First, carbapenemase-producing Enterobacteriaceae may be only slightly less susceptible to carbapenem antibiotics, requiring laboratories to have a higher sensitivity when testing for marginal strains. Second, most enzyme-producing bacteria are primarily resistant to β-lactam antibiotics, but those carrying the OXA-48 gene may still be sensitive to cephalosporin antibiotics, such that problems may arise when applying automated drug susceptibility detection systems. This suggests that the requirements of carbapenemase testing are high, and not many laboratories in China have the ability to do this testing, should be strengthened and standardized, while those who wish to carry out this test should be specially trained to ensure the quality of the test. The country should also establish a reference laboratory base to the United Kingdom as well, to help carry out carbapenemase-producing tests around the country, which should include: ① confirming the antimicrobial spectrum; ② identifying the type of carbapenemase; ③ confirming the outbreak of the epidemic; ④ tracking the clone of the disseminated resistant strain when the resistant strain is prevalent.
Not all gram-negative bacteria clinically need to be tested for carbapenemases, and the recommendations of the UK guidelines are available for our reference. They suggest that the following do not need to be investigated: (i) Aspergillus spp. resistant to imipenem only, which have inherent hypersusceptibility; (ii) Enterobacter spp. resistant to cephalosporins and low levels of ertapenem but sensitive to imipenem and meropenem, which usually produce both AmpC enzymes and have reduced membrane permeability. (iii) Carbapenem-resistant Fusobacterium or Pseudomonas aeruginosa, unless these bacteria have high levels of resistance (e.g., can grow on carbapenem media) or a positive ethylenediaminetetraacetic acid (EDTA)-imipenem synergy test, the latter suggesting the presence of metalloenzymes. The suitability of these suggestions for our situation has yet to be confirmed by our own data.
At present, carbapenemase detection methods are “Hodge” test (see Figure 3) and synergistic test, but these methods do not have a clear interpretation of the standard, so for reference only.
1. “Hodge” (Cloverleaf) test (Figure 3): ① Escherichia coli NCTC10418
(or ATCC25922) spread all over the agar plate for drug sensitivity paper test; ② in the form of three arms of 120° evenly divided the tested strain cut into or formed a deep stripe from the center of the plate inoculated into the agar; ③ will contain imipenem, meropenem and ertapenem 10ug of paper tablets were placed at the end of the three arms; ④ inhibition circle depression that indicates that the tested strain antagonistic carbapenem antibiotics. It is worth noting that the reading of the results is affected by subjective factors, and AmpC enzyme can show weak false positive results.
2. Synergy test (Figure 4): ① metallo-carbapenemases (IMP, NDM, VIM) can be inhibited by EDTA or 2,6-pyridinedicarboxylic acid; ② synergy between carbapenems and EDTA suggests the presence of metallo-β-lactamases (MBL), which can be detected by Etests or double paper test; ③ note that Pseudomonas aeruginosa and Acinetobacter baumannii often show false-positive results, but Enterobacteriaceae are rare. KPC enzyme is inhibited by boric acid, and the synergistic effect of boric acid paper slices and imipenem double paper slices suggests the presence of KPC.
III. Measures to reduce the risk of carbapenemase dissemination
The most effective way to eliminate carbapenemase-producing bacteria is to prevent the development of drug resistance, including antibiotic stewardship, infection control, and rational antibiotic use. The current situation in China tends to focus on treatment rather than prevention, and even when preventive measures are mentioned, they are abstract and lack operability. The UK guidelines list many specific preventive measures, such as emphasizing the involvement and support of leadership and management, and specific infection control measures, which are worthy of our reference.
The management of antimicrobial drugs is an important measure to reduce drug-resistant bacteria, which is a missing item in China, and even if there are regulations, they are often in name only and difficult to implement. The UK guidelines recommend the formation of local multidisciplinary teams to ensure the implementation of various management measures, thereby promoting the rational and safe use of antimicrobial drugs and reducing the occurrence and spread of drug resistance. Recently, the Ministry of Health of China is going to introduce “antibacterial drug management methods”, which will have a profound impact on the rational application of antibiotics in China.
Endoscopy has become an important tool for clinical diagnosis and treatment, and the UK guidelines particularly emphasize the impact of endoscopic procedures on infection, as it is known that endoscopy and related procedures can lead to the spread of drug-resistant bacteria, for example, several cases of endoscopy-associated transmission of carbapenem-resistant strains have been reported in the UK and France. Therefore, our country should also educate relevant staff to recognize these risks and adopt careful procedures, and special attention should be paid to disinfection or protection of other equipment used with the endoscope, such as cameras, which are usually not routinely disinfected.
IV. Treatment of carbapenemase-producing bacterial infections
Most carbapenemase-producing bacteria are extremely resistant to drugs, and there are limited drugs that can be applied. In 2010, the Ministry of Health of China issued the “Guidelines for the Treatment of NDM-1 Pan-resistant Enterobacteriaceae Infections (Trial Version)”, which recommended six classes of drugs, including tigecycline, polymyxin, carbapenems, aminoglycosides, fluoroquinolones and fosfomycin, for the treatment of infections caused by NDM-1 bacteria, and formulated treatment plans for patients with mild to moderate and severe infections, but whether it is reasonable requires clinical practice However, clinical practice is needed to test whether they are reasonable. For example, aminoglycosides and fluoroquinolones, which are usually resistant to NDM, are recommended as drugs in China’s treatment guidelines, but the introduction is very simple and not very operative. The UK guidelines give a detailed description of the recommended therapeutic drugs, including advantages and limitations, and give indications for trial under specific conditions for drugs that are usually insensitive, which can be used for our reference in treatment, as follows.
1. β-lactams: usually bacteria are all resistant to this class of drugs, but certain drugs can be considered for trial: ① Aminotrans: stable to metallo-carbapenemases (including IMP, VIM and NDM), but most enzyme-producing bacteria are resistant due to simultaneous production of AmpC or ESBL; Aminotrans is unstable to non-metallo-carbapenemases such as OXA-48 and KPC. ②Ceftazidime, cefotaxime and aminotransomide: still active against Enterobacteriaceae that produce OXA-48 but not AmpC or ESBL; ③Timocillin: relatively stable against KPC enzymes, but most MIC values are slightly outside the permissible dose range (2g, q12h); ④β-lactamase inhibitors: all current drugs cannot inactivate carbapenemases; ⑤Carbapenems: resistant to some Low-level (<4mg/l) resistant enzyme-producing bacteria still have activity.
2. Aminoglycosides: usually bacteria are all resistant to this class of drugs: ① NDM-1 producing strains: usually contain 16S-rRNA methylesterase, the latter makes the bacteria resistant to the current clinical aminoglycosides can be used; ② KPC producing Klebsiella pneumoniae (ST258): most sensitive to gentamicin, but not to other aminoglycosides; ③ KPC producing, VIM, IMP and OXA -48 enzyme strains: resistance to aminoglycosides is highly variable due to the action of multifunctional modifying enzymes. Isopamisin is effective against some isolates, although these isolates are resistant to other aminoglycosides.
Polymyxin, tigecycline, and fosfomycin: are the most frequently effective drugs tested in vitro, but all have limitations. The dose needs to be adjusted according to the patient and the site of infection, following the principle of “highest safety” rather than “lowest possible effectiveness”, and the course of treatment should be standardized according to the type of infection.
It is not available in the UK, but pharmacists can import the drug.
Other: A few isolates are sensitive to other antibiotics such as chloramphenicol, ciprofloxacin, and cotrimoxazole. However, most enzyme-producing bacteria are resistant to these drugs.