Professor Yang Fan

Doctor of Medicine

Director of Infection Control Department, and Chief Physician of Institute of Antibiotics, Huashan Hospital, Fudan University

Secretary-general of Chinese Society of Bacterial Infection and Resistance Committee, Medical Association

Chairman-elect of Infection and Chemotherapy Branch, Shanghai Medical Association

Q1. The use of antimicrobials is not merely a medical challenge, but a complex problem involving social policy. In the past few years, the Chinese health administration has increased the efforts in managing the use of antimicrobials – leading to many fruitful results from a series of strategies. Experts like yourself have contributed immensely to these efforts. What are the strategies implemented and their consequences in controlling the use of antimicrobials in China?

The Chinese health administration has vigorously promoted the rational use of antimicrobials since 2004. From 2011, guidance documents have been published annually. These reflect on China’s emphasis and determination in ensuring rational use of antimicrobials, and have indeed observed ideal outcomes from these efforts.

Firstly, the awareness towards rational use of antimicrobials among medical staff and hospital management has greatly increased. The rational use of drugs is now internalised and has become the responsibility of every individual.

Secondly, we have established two massive monitoring systems: a monitoring network for the use of antimicrobials, and another monitoring network for antimicrobial resistance. More than 3,000 hospitals are participating in these surveillance networks – while some regions may have only a few hospitals involved – the overall number of institutions involved are representative of the situation in China. Although there are still rooms for improvement in the quality of data, these two monitoring systems have provided evidence for the management of antimicrobial use and the prevention of antimicrobial resistance.

Thirdly, we have introduced large scale training projects, such as the Peiyuan, Peiying, and Peiwei Projects – to train professional talents. The Peiyuan Project is named after the Chinese philosophy of “Pei Yuan Gu Ben” (to strengthen the foundations). The project mainly tackles the diagnosis and treatment of infectious diseases commonly seen by infectious diseases physicians, including hepatitis; issues surrounding the diagnosis and treatment of bacterial and fungal infections; and nurturing the physicians’ abilities in managing these infections. Subsequently, the launching of the Peiying Project targets clinical pharmacists involved in the management of infectious diseases, whereas the Peiwei Project targets clinical microbiologists. All three projects are collectively known as the Peilifang and have successfully trained more than 8,000 professionals to-date. These professionals have become the backbone of the management of bacterial and fungal infections – bringing our nation’s rational use of antimicrobials to higher levels.

Fourthly, we have observed improvement in many aspects of the use of antimicrobials, including the usage rate among outpatients and inpatients, usage rate of prophylactics, as well as the effectiveness of antimicrobials.

Q2. A major reason for the strict control of antibiotics use in China is the emergence of antimicrobial resistance. What are the current trends of drug resistance in China?

The current global and local trends in antimicrobial resistance are worrying. The rate of antimicrobial resistance in many common pathogens is high – with carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant Acinetobacter baumannii showing disturbing rates, therefore resulting in greater challenges in diagnosis and treatment. This phenomenon is due to the lack of infection control measures. Furthermore, the overuse of antibiotics may lead to new problems during the introduction of medical reforms.

For example, the hospital bed density in China is high; many hospitals allocate 4 patients or up to 8 patients in a room. Sometimes, they may even need to add more beds or even place beds along the corridors. The close proximity of beds increases the risk of cross-infection between patients. In addition, the shortage of medical staff suggests the lapse in task management. Thus, we hope to improve infection control measures for the prevention of nosocomial infections and emergence of antimicrobial-resistant bacteria. Such strategy would be more effective and economical than to treat nosocomial infections and to curb the spread of antimicrobial-resistant bacteria when they arise. With improving efforts in the country, these improvements are achievable.

Another example is that Chinese government encourages centralised purchasing. The purpose of centralised purchasing is to lower medical costs. While we are heading towards the right direction, I do hope that the various administrations could have better coordination to ensure the minimal use of antibiotics. This would require good coordination to avoid unnecessary use of antibiotics following bulk purchases. In addition, the low costs of drugs can also affect the quality and supply of drugs purchased – leading to irrational upgrade of antibiotics. For instance, following the collective purchase of meropenem by a particular province, the price of the drug dropped to 9 yuan per bottle – a much cheaper price compared with other cephalosporins. However, many physicians are under the misconception that as long as the average daily treatment cost remains unchanged, using a broad-spectrum antibiotic such as meropenem is safer and more effective. This has led to significant increase in the use of meropenem. As such, it is important to instil specialist knowledge and to increase the awareness of the rational use of antimicrobials.

Q3. What should hospitals consider when assessing the formulary for antibiotics? What are issues in our antibiotic use? The World Health Organization (WHO) list of essential medicines covers the accessibility of global drugs and unbalanced regional development. What is the significance of this list to the clinical practice in China?

Historically, many drugs with poor therapeutic effects or poor safety profiles are not released in the markets. The National Health Commission strictly limits the list and types of antibiotics in hospitals to improve the formulary structure. We should ensure a wide variety of drugs and to choose those that are safe, effective, and more economical. At the same time, we need to correct the misconception that “less variety means better management” to ensure rational use in clinical practice. Another problem is the balance between original drugs and generic drugs. Keeping original drugs encourages drug research and development. Patients with financial ability are also willing to pay a higher price. On the other hand, generic drugs provide an opportunity for patients without the financial ability to use similar drugs, and present opportunities for local enterprises to expand and grow. The price competition between generic drugs and original drugs will reduce the price of original drugs. Thus, having two sources for one product –original and generic – is a more ideal combination.

There is a problem concerning the use of antibiotics in China. For example, there is low usage of penicillin. On the other hand, the use of special drug class (equivalent to restricted class in other countries）like carbapenems and tigecycline are high and on the rise. This structure is not rational and goes against the goals of safety, efficacy, and economical treatment for patients, as well as antimicrobial resistance containment. This phenomenon warrants extra attention and further improvement.

The WHO list of essential medicines suggests the Access, Watch, and Reserve classification. Ideally, the Access category makes up 60% of drug use. We are currently far from WHO’s requirements and will use this list and classification to improve on antibiotics usage. However, a large part of WHO’s categorisation rides on the accessibility of drugs as well as imbalances in regional development. Some of the categorisations do not match with antimicrobial resistance and societal developmental standards in China. For example, ampicillin and gentamicin are categorised under Access. However, the former has high resistance rate, while the latter has many side effects, therefore, I do not think they are suitable. We should adjust the WHO categorisation based on our national circumstances, such as antimicrobial resistance, economic level, and drug accessibility to achieve the goals of safety, efficacy, economical treatment for patients, and antimicrobial resistance containment.

Q4. Each class of antibiotics is different. Using quinolones as an example, can you describe the differences between various antibiotics and their antimicrobial activities?

The most common quinolones are levofloxacin, ciprofloxacin, and moxifloxacin. Their antibacterial activities are different. Ciprofloxacin is stronger against Gram-negative bacteria but performs poorly against Streptococcus; levofloxacin and moxifloxacin are respiratory quinolones and are more effective against Streptococcus pneumoniae; moxifloxacin performs well against Gram-positive bacteria, anaerobic bacteria, atypical pathogens, and Stenotrophomonas maltophilia. On the other hand, levofloxacin is also effective against both Gram-positive and Gram-negative bacteria such as S. pneumoniae and Pseudomonas aeruginosa.

They also differ in terms of pharmacokinetics. For example, levofloxacin has superior bioavailability while ciprofloxacin is much poorer. Also, levofloxacin is primarily excreted through urine while most of the ciprofloxacin and moxifloxacin are excreted through the biliary tract. When treating urinary tract infections, even though the antimicrobial activity of ciprofloxacin is more effective against Gram-negative bacteria, levofloxacin should be prioritised because the concentration of levofloxacin in the urinary tract is higher than that in ciprofloxacin. This will offset the disadvantages of in vitro antimicrobial activity.

New quinolones are still being discovered. For example, nemonoxacin has increased antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive bacteria. Meanwhile, sitafloxacin has been shown to be more effective against Escherichia coli and P. aeruginosa.

Q5. What are the problems concerning skin testing with β-lactams in China? How can we standardise the testing?

Currently, the screening for allergy history is poor in China. Problems such as excessive skin test indicators, non-standardised operation of skin test, and mistakes in result analysis are a huge waste of resources, delaying patient’s treatment, limiting their antibiotic options, and leads to structural irrationality in antibiotic usage as well as indirectly increases the rate of antimicrobial resistance. This is a major problem in improving the rational use of antibiotics. Thus, we advocate for accurate analysis of skin test, avoid excessive skin test, and through improving β-lactams skin test, help to ensure rational use of antibiotics.

Currently, through the hard work of specialists from various disciplines such as infectious diseases, allergic reaction, clinical pharmacy, and nursing, the National Health Commission is in the midst of organising and authoring the “Guidelines for β-lactam antibiotics skin test”. The strategies for improving the skin test include recognising and addressing the lack of awareness of skin test among medical staff; gradual amendment of relevant regulations and manuals; improving education as well as changing beliefs. The first step would be removing cephalosporin skin test screening, followed by narrowing the indication of penicillin skin test and improving it – taking into consideration the big picture of the current situation and not irrelevant details. Under the support of many capable experts and healthy officials, and the leading role of many famous hospitals, cephalosporin screening is being abolished in many hospitals. β-lactam antibiotics skin test is definitely advancing in the right direction.

References

1. Status report on antimicrobial management and antimicrobial resistance in China (2018)
2. Liu Yinqi et. al.. The policy evolution and revelation of antibiotic resistance management in China. China Health Policy. 2019;12(5):44
3. Administrative measures for clinical application of antimicrobials (Ministry of Health, Order No. 84) Status report on antimicrobial management and bacterial resistance in China.
4. 2018 CHINET Monitoring antimicrobial resistance in China
5. https://www.who.int/medicines/publications/essentialmedicines/en/
6. One Health strategy for antibiotic resistance prevention and control. Chinese Journal of Biotechnology. 2018;34(8):1361