Professor Yang Fan

Introduction: Rational use of antimicrobial drugs under viral-bacterial co-infection in the context of the COVID-19 epidemic.

With the liberalisation of the COVID-19 epidemic prevention/control policy and the publication of the “General Plan for the Implementation of “Category B” Management of COVID-19 Infections”¹, the number of critically ill hospital patients is increasing day by day, and the goal of prevention and control work is precisely directed towards “health protection and prevention of severe illness”. It is worth noting that the rational use of antimicrobial drugs in the treatment of patients with COVID-19 infections is also a great challenge.

Recently, “Medical World” invited Professor Yang Fan from Huashan Hospital, Fudan University, to discuss in detail the indications, selection, and precautions for the use of antimicrobial drugs in patients infected with COVID-19 based on the principles, experience, and available evidence of antimicrobial drug use.

Q1. The Omicron variant has become the major prevalent strain worldwide, how do you think its virulence has changed? The number of patients with severe COVID-19 infection is increasing in clinical practice. Do you think this phenomenon is related to the change in virulence of the new strain?

Since the adjustment of the epidemic prevention/control policy, the absolute number of patients with severe COVID-19 infections is higher. However, the prevailing professional opinion is that the Omicron strain is less virulent than previous strains, including the original one.

The higher-than-expected number of severe COVID-19 infections in the second half of 2022 is mainly owing to the low infection rate among the population in the past three years of strict prevention and control policies in China, paired with the fact that the vaccinated population has passed the optimal protection period and failed to form an effective herd immunity barrier. Other factors include the general lack of indoor ventilation in winter, the high contagiousness of omicron, and the extremely high infection rate in a short period of time. Even if the incidence of severe disease is not high, the absolute number of severe cases cannot be overlooked. This situation is compounded by the inadequate vaccination rate of the elderly, people with underlying diseases and other high-risk groups, and the relative strain on medical resources caused by medical infections. However, through the hard work and dedication of the medical staff, the most difficult period has been overcome.

Q2. Under what circumstances can antimicrobial therapy be initiated in the treatment of COVID-19 patients? How are antimicrobial treatment regimens selected for patients in different treatment sites such as outpatient clinic, emergency room, general ward, and intensive care unit (ICU)?

In our efforts to standardise the use of antimicrobial drugs in COVID-19 patients, the Institute of Antibiotics has issued the “Principles for the Use of Antimicrobial Drugs in COVID-19 Patients.” Special attention should be given to the background of the release of this principle: (1) there is a lack of authoritative guidelines to draw on, and we have based this principle mainly on general rules, experience and available evidence in the diagnosis and management of bacterial infections; (2) this is only one opinion and the drug types are based only on our hospital’s antimicrobial drug list; and (3) there is currently widespread misuse of antimicrobial drugs in the treatment of COVID-19 infections.

According to relevant foreign studies, only a minority of COVID-19 patients have early coexisting bacterial infections. Most patients present with a small amount of yellow sputum, a mild increase in white blood cells or a small amount of patchy shadow and consolidation on lung computed tomography (CT) in the early stages of COVID-19 infections, but these symptoms do not indicate the presence of a bacterial infection, and viral infections can also cause interstitial lung changes and a solid or patchy lung CT.

Due to the lack of a basis for patient stratification, we stratified infected patients only by outpatient, emergency and emergency inpatient, and inpatient settings, rather than by “mild” and “severe” infections, to avoid confusing severe bacterial infections with severe viral infections. Oral medication is recommended for outpatients and emergency patients, while intravenous administration is recommended for emergency inpatients and inpatients. For the selection of specific antimicrobial drugs, it is recommended to refer to the treatment guidelines for community-acquired pneumonia (CAP)² and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP)³, depending on the site and time of onset.

Specific recommendations focus on β-lactams and respiratory quinolones, which are readily available, commonly used and relatively safer than other options.

Among the oral preparations of β-lactam antibacterial drugs, the main recommendation is amoxicillin-clavulanic acid and other drugs with better antibacterial effects against Streptococcus pneumoniae and Haemophilus influenzae. In terms of intravenous preparations, third- and fourth- generation cephalosporins and enzyme inhibitor combinations (such as amoxicillin-clavulanic acid, etc.) are available. We emphasise that carbapenems should be restricted to patients with established drug-resistant negative bacterial infections or with risk factors for drug-resistant Gram-negative bacteria.

The widespread misuse of antimicrobial drugs not only increases the cost of treatment, the occurrence of adverse effects and the risk of bacterial drug resistance, but may also lead to superinfection. It has been reported abroad that a high proportion of fungal superinfections such as Aspergillus and Trichophyton are caused by the inappropriate application of broad-spectrum antimicrobials and hormones to patients with severe COVID-19 infections; Candida oral infections, for example, are very common among our current elderly COVID-19 patients.

Q3. Many hospitals have included respiratory quinolones in the initial empirical antimicrobial regimen as the first choice in their COVID-19 infection diagnosis and treatment plans. Could you please talk about the value of respiratory quinolones, such as levofloxacin, moxifloxacin, nexofloxacin, and cetefloxacin, in anti-infective treatment during the COVID-19 epidemic?

Respiratory quinolones have the advantages of good bioavailability, high tissue concentration and broad-spectrum coverage of a variety of common respiratory pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, Enterobacteriaceae, Chlamydia, Mycoplasma and Legionella. In situations of resource constraints in medicine, oral preparations of respiratory quinolones such as levofloxacin, moxifloxacin and cetafloxacin can effectively reduce the burden on current healthcare facilities.

Recently, the number of visits to healthcare facilities has increased rapidly, and many emergency patients are unable to access intravenous therapy. Respiratory quinolones such as levofloxacin are not only available in oral form, but also have the area under the curve (AUC) for intravenous that is very close to the oral AUC, which is more conductive to the clinical realisation of out-of-hospital sequential treatment, enhancing patient comfort and reducing the pressure on healthcare facilities.

Q4. For patients with underlying respiratory disease (e.g. patients with bronchiectasis, chronic obstructive pulmonary disease, etc.), how do we determine the timing of initiating antimicrobial therapy after the patients are infected with COVID-19?

The indications for nonsurgical antimicrobial prophylaxis are strictly limited, such as the need for prophylaxis in the prevention of rheumatic fever and in patients with organ transplants. However, in the absence of indications for the use of antibiotics, the early application of antimicrobial drugs is not recommended for people at high risk of bacterial infection, such as patients with bronchiectasis and chronic obstructive pulmonary disease. Patients should be closely monitored clinically, and antimicrobial regimens should be initiated after evidence of bacterial infection is detected.

Q5. For patients who have tested negative for COVID-19 infection, what aspects do we need to prevent and control to avoid secondary viral infection and bacterial infection?

Patients with COVID-19 infections are advised to rest and keep warm after their nucleic acid results turn negative, as well as take daily precautions and complete COVID-19 vaccination under the guidance of medical staff. If there is concern about secondary bacterial lung infection, the elderly, children, and immunocompromised patients should be vaccinated against Streptococcus pneumoniae to reduce the risk of secondary bacterial infection.

References
1. National Health Commission of the People’s Republic of China. Notice on the issuance of the general plan for the implementation of the “Category B” management of COVID-19 infection. http://www.nhc.gov.cn/xcs/zhengcwj/202212/e97e4c449d7a475794624b8ea12123c6.shtml

2. Qu Jieming, Cao Bin. Guidelines for the diagnosis and treatment of community-acquired pneumonia in adults in China (2016 edition) [J]. Chinese Journal of Tuberculosis and Respiratory Medicine, 2016, 39(04): 253-279.

3. Shi Yi. Guidelines for the diagnosis and treatment of hospital-acquired pneumonia and ventilator-associated pneumonia in adults in China (2018 edition) [J]. Chinese Journal of Tuberculosis and Respiratory Medicine, 2018,41(04):255-280.