Ye Feng, Chief Physician and Doctoral Advisor
Deputy Head of Respiratory Medicine at The First Affiliated Hospital of Guangzhou
Medical University/Guangzhou Institute of Respiratory Health
Member of the Infections Assembly, Chinese Thoracic Society, Chinese Medical Association (7^th to 10^th Term)
Member of the Respiratory Infectious Diseases Working Committee, Chinese Association of Respiratory Physicians, Chinese Medical Doctor Association
Member of the Academic Committee for Respiratory Infections, Respiratory Diseases Assembly, Chinese Geriatrics Society
Member of the Expert Committee for Comprehensive Quality Control of Prevention and Treatment of Tuberculosis in China
Member of the Working Committee of Appropriate Application of Antimicrobial Drugs, Chinese Hospital Association
Leader of the Infectious Diseases Group, Executive Member of the Thoracic Society, Guangdong Medical Association
Leader of the Anti-Infectives Group, Executive Member of the Assembly for the Prevention and Control of Infectious Diseases in Hospitals, Guangdong Medical Association
Deputy Head of the Expert Committee for Respiratory Medicine, Guangdong Pharmaceutical Association
Deputy Head of the Expert Committee for Respiratory and Critical Illnesses, Guangdong Women’s Medical Association
Deputy Head of the Anti-Infectives Assembly, Guangdong Precision Medicine Application Association
Executive Member of the Tuberculosis Society, Guangdong Medical Association
Member of the Committee for Pharmaceuticals Management and Drug Treatment in Guangdong
Member of the Expert Advisory Committee for Vaccination Planning, Health Commission of Guangdong Province

Despite healthcare advances in recent years, the emergence of antimicrobial resistant (AMR) pathogens continue to be a major health concern. Our research and development in AMR still lag behind the rapid emergence of AMR pathogens. This article provides a brief insight into the current trends in AMR in respiratory tract infections (RTIs) – highlighting important causative pathogens and optimisation of antimicrobial treatments.

Q1. China has stepped up on the management of antimicrobial drugs in recent years, but antimicrobial resistance continues to pose significant challenges. Please give us a brief background of the common antimicrobial drugs used in respiratory tract infections and the patterns of AMR.

The most common pathogens in community-acquired pneumonia (CAP) are Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. According to the 2019 surveillance results provided by the China Antimicrobial Surveillance Network (CHINET), H. influenzae, S. pneumoniae and M. catarrhalis make up 15.4% of all detections in secondary hospitals, which is higher than the rate of detection of 7.89% in tertiary hospitals ^(1,2).

The resistance rate of H. influenzae to ampicillin is 60% and surveillance data spanning across 15 years from 2005 to 2019 have shown an overall increasing trend. However, the resistance rate of M. catarrhalis to amoxicillin and clavulanic acid is less than 5%. Penicillin resistance in S. pneumoniae in children has increased from 5.4% in 2006 to 21.9% in 2013, but we see a gradual downward trend from then on. Children make up 71.7% of non-meningitis S. pneumoniae cases, of which penicillin susceptibility tests showed that 2.9% are penicillin-intermediate S. pneumoniae (PISP) and 0.5% are drug-resistant S. pneumoniae (DRSP). These figures are higher in adults, with penicillin susceptibility tests showing that 3.5% are PISP and 1.0% are DRSP. Penicillin-resistant S. pneumoniae (PRSP) has a 4.5% and 0% ^(1,7) resistance rates to levofloxacin and moxifloxacin respectively. It is noteworthy that S. pneumoniae has shown long-term resistance rate above 90% to macrolides and clarithromycin in secondary and tertiary hospitals ^(1,7). The China Antimicrobial Resistance Surveillance System (CARSS) has provided worrying data about drug resistance in the abovementioned pathogens even in outpatients. The resistance rate of H. influenzae to ampicillin has risen from 37.5% in 2014 to 55.6% in 2019. Non-meningitis strains of S. pneumoniae have maintained a resistance rate of above 90% to erythromycin, and a resistance rate between 86.2% and 90.7% to clindamycin ⁽⁸⁾.

Five of the most common pathogens in hospital infections – Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus – are important pathogens requiring surveillance. CHINET surveillance data from 2005 to 2014 showed that the number of E. coli strains that produce extended spectrum beta-lactamase (ESBL) remain at a steady rate of 51.7% to 55.8% while ESBL-producing strains of K. pneumoniae have dropped from 39.1% in 2005 to 29.9% in 2014 ⁽⁹⁾. Both E. coli and K. pneumoniae have shown overall decreasing rates of resistance to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam in the same time period. E. coli continue to maintain high sensitivity (97.8%) towards carbapenems. While the meropenem-resistant strain of K. pneumoniae has increased drastically from 2.9% in 2005 to 29.5% in 2018, it has decreased to 26.8% in 2019. The same 2019 data also showed that K. pneumoniae has a resistance rate of 3.6% and 1.8% towards tigecycline and polymyxin respectively ⁽²⁾. P. aeruginosa have shown an overall decreased resistance to tested antimicrobial drugs – with resistance rates of 27.5% and 23.5% towards imipenem and meropenem respectively in 2019, and resistance rates towards ciprofloxacin and levofloxacin were 18.9% and 20.1% respectively in 2018 ^(2,10). A. baumannii have shown significant increase in drug resistance, with CHINET and CARSS data showing a consistent resistance rate above 50% for most antimicrobial drugs ^(11,12). Despite exhibiting lower resistance to cefoperazone/sulbactam and minocyline, CHINET data showed that the resistance rates in A. baumannii have risen from 5.4% and 31.9% to 39.6% and 51.1% respectively. It has shown increased resistance to imipenem and meropenem between 2005 and 2019 from 31.0% and 39% to 73.6% and 75.1%, respectively. However, there is substantial difference in drug resistance rates across regions ^(2,12,13) for the A. baumannii, with its strains exhibiting resistance rates of 3.6% and 2.3% to tigecycline and polymyxin in 2019. The number of methicillin-resistant S. aureus (MRSA) strains have decreased from 69% in 2005 to 31.4% in 2019, and they remain highly sensitive (100%) to gylcopeptides and linezolids treatments ^(2,4-6,9). A general comparison with tertiary hospitals showed that secondary hospitals tend to have a lower resistance rate of 25.7% in the Klebsiella species, as well as fewer cases of carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant P. aeruginosa (CRPA) at 2.8% and 18.4% respectively. However, secondary hospitals have quite a high number of carbapenem-resistant A. baumannii (CRAB) at 47.5%. Meanwhile, there are slightly more cases of MRSA in 2019, but secondary hospitals have yet to find cases of vancomycin-resistant Enterococcus ^(1,2).

Q2. What are some of the pathogens that we should take note of when treating respiratory tract infections?

The above-mentioned pathogens are primarily from various hospital departments, with samples taken from respiratory tract secretions, pleural effusions, blood, urine, cerebrospinal fluids, etc. Are these data different from the treatment of respiratory tract infections? CARSS data between 2014 and 2019 showed that brochoalveolar lavage fluid culture were mostly Gram-negative bacteria. The top five cultured bacteria are P. aeruginosa (19.1%), A. baumannii (16.6%), K. pneumoniae (16.6%), S. aureus (7.8%) and S. pneumoniae (6.2%). The first three bacteria are common pathogens seen in CAP – with high fatality rate as our treatment options are increasingly limited following an increase in carbapenem-resistant strains ^(15-17). Therefore, our current focus is on species with Gram-negative bacteria exhibiting multiple drug resistance relating to hospital-acquired pneumonia (HAP) and/or ventilated-associated pneumonia (VAP), especially treatment for CRE and non-fermenters like CRAB and CRPA.

Some of the recent successful research and development of drugs that target carbapenem-resistant Gram-negative bacteria include tigecyline (ineffective towards P. aeruginosa), polymyxin, and ceftazidime/avibactam ^(18-21). Despite development and use of new drugs, CRE continues to spread with increased transmissibility, among which CRKP has shown increased resistance to polymyxin. The resistance rate of Enterobacteriaceae to polymyxin has increased to 15% between 2009 to 2012 in the West ⁽²²⁾. A multicentre study in Europe has shown that CRKP has a polymyxin resistance rate of up to 28.3% ⁽²³⁾. CRE poses a serious mortality risk on patients, as data have shown that CRKP has a total fatality rate of 41.14% ⁽²⁴⁾. CHINET local data between 2011 and 2014 has shown that A. baumannii is less resistant to polymyxin
(0-6.5%), but the data sets differ between hospitals with multidrug and/or extensive resistance (MDR/XDR). For instance, one Chongqing hospital showed MDR A. baumannii with a polymyxin resistance rate of 11.7% while XDR A. baumannii in Henan showed an average polymyxin resistance rate of less than 2% ⁽²⁵⁾. Most MDR and XDR A. baumannii across regions and countries maintain a sensitivity above 95% towards polymyxin, but some countries like Iran have shown a resistance rate of up to 16% ⁽²⁵⁾. A multicentre retrospective study has shown significant relevance between pneumonia or sepsis caused by MDR A. baumannii and the resulting fatality rate ⁽²⁶⁾ – a phenomenon that warrants our focus.

Q3. What suggestions do you have regarding the optimisation of antimicrobial treatment pertaining to these pathogens?

When treating CAP with antimicrobials, we should consider the high drug resistance rate of S. pneumoniae to macrolides. This means that only regions with a lower drug resistance can consider empiric therapy ⁽²⁷⁾.

As for the choice of antimicrobials for Gram-negative bacteria exhibiting MDR, the rule of thumb is to establish a local drug sensitivity database in order to obtain an accurate evaluation of the risk factors for MDR bacterial infections. We should avoid antimicrobials with a high resistance when considering empiric therapy for MDR Gram-negative bacterial infections. At the same time, it is imperative to determine the cause and rate of resistance as soon as possible in order to select an appropriate drug based on the drug sensitivity results and the minimum inhibitory concentration. Combination therapy might be necessary, an increase in the dosage or duration of medication, or pairing it with inhaled medications might be an option. Departments that are able to conduct therapeutic drug monitoring (TDM) should adjust the dosage and frequency based on the TDM results.

Regarding empiric therapy for the above-mentioned Gram-negative bacterial infections, carbapenems (excluding ertapenem) can be a choice in regions that have high carbapenem sensitivity ⁽²⁸⁾. When treating patients at risk of MDR who may have a high mortality risk, the Chinese guidelines for HAP/VAP-related pneumonia treatment (2018 edition) suggests a combination therapy of two different classes of antimicrobials, while polymyxin and tigecycline should only be used in patients with XDR Gram-negative bacterial infections ⁽²⁹⁾.

When determining the choice of targeted antimicrobial therapy for bacteria exhibiting MDR, there are different strategies depending on the causative pathogens. A CRE-focused treatment will mainly consist of polymyxins, tigecycline and/or ceftazidime/avibactam. These may be used in combination with fosfomycin and/or aminoglycosides for combination therapies that may include carbapenems. The dominant carbapenem in China is K. pneumoniae carbapenemase (KPC), so we may choose to go with ceftazidime/avibactam ⁽²⁹⁾. Meta-analysis has shown that ceftazidime/avibactam treatments for Gram-negative bacterial infections are comparable with the control group ⁽³⁰⁾. We can use a combination therapy for MDR P. aeruginosa infections; an intravenous therapy ocmbined with inhalation of aminoglycosides or polymyxin E for XDR infections; polymyxins or a polymyxin-based combination therapy for CRPA infections among other strategies ⁽²⁹⁾. When treating with piperacillin/tazobactam, we may increase the dose frequency to once every six hours for a maximum of three hours consecutively. The new drug, sitafloxacin, has shown to be effective against levofloxacin-resistant P. aeruginosa, so it may be considered as one of our treatment options ^(31,32). When treating XDR/PDR A. baumannii, consider sulbactam or a sulbactam-based combination therapy; alternatively, consider a combination therapy of polymyxins or tigecycline. We may increase the dosage of sulbactam to 6-8 g/d; we can also increase the dosage and intravenous duration of carbapenems ⁽²⁹⁾. It’s imperative to note that meta-analysis has shown that a combination therapy of sulbactam, polymyxins and tigecycline to treat MDR A. baumannii bacterial infections have the highest clinical recovery rate compared to other forms of treatment, but more validation is required to achieve statistical significance ⁽³³⁾.

As for bacteria with MDR, the industry is in the midst of developing medication that combines enzyme inhibitors and carbapenems that have yet to be approved in China. Potential combinations include imipenem/cilastatin/relabactam and meropenem/vaborbactam, which may become available in the future.

In general, we are facing a huge challenge of drug resistance in pneumonia at the moment, especially when treating carbapenem-resistant Gram-negative bacteria such as K. pneumoniae and A. baumannii. Treatment options are limited, which include tigecycline (which is not effective against P. aeruginosa), polymyxins, and ceftazidime/avibactam. Because of the high fatality risk, it is crucial to identify the causes promptly, optimise and implement targeted antimicrobial therapies which may include selecting drugs of high sensitivity, raising the dosage, introducing combination therapy, and pairing with inhaled medication.

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