Status of Levofloxacin in the perspective of HAP/VAP Guidelines

17 April, 2020

Professor Shi Yi

Professor, Chief Physician, Doctoral Supervisor, Postdoctoral Supervisor
Fellow of the American College of Chest Physicians
Standing Committee Member of Respiratory Physician Branch and Deputy Chairman of Respiratory Infection Working Committee, Chinese Medical Doctor Association
Deputy Leader of Infectious Disease Group, Chinese Medical Association Respiratory Branch
Chairman of the seventh and eighth sessions of Jiangsu Medical Association Respiratory Branch
Standing Committee Member of Professional Committee of Infectious Diseases, Chinese Medical Education Society
Standing Committee Member of Professional Committee on Respirology, Cross-Strait Medicine Exchange Association
Standing Committee Member of Respiratory Branch and Chairman of Infection Academic Committee, Gerontology Society of China

Q1: How are hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) defined and what are the differences between guidelines in
different countries?Interview content

Hospital-acquired pneumonia (HAP) refers to pneumonia that newly occurs after 48 hours of admission in patients who do not receive invasive mechanical ventilation during hospitalization and are not in the incubation period of pathogenic infection. Ventilator-associated pneumonia (VAP) refers to pneumonia that occurs after 48 hours of mechanical ventilation in patients with endotracheal intubation or tracheotomy. Pneumonia that occurs within 48 hours after mechanical ventilation withdrawal and extubation also falls in the scope of VAP[1].

HAP was previously considered to include VAP and healthcare-associated pneumonia (HCAP)[2]. Patients with HCAP are mainly those in long-term hemodialysis, living in long-term care facilities, and in close contact with medical institutions. Their risk factors and prognosis for drug-resistant bacterial infections are different compared with community-acquired pneumonia (CAP). With further in-depth study, it is found that HCAP patients show significant clinical differences ranging between HAP and CAP. Therefore, it is inappropriate to classify HCAP as HAP. In recent years, China, the United States and Europe have abandoned this concept and HAP guidelines no longer include HCAP[1][3]. However, considering a high proportion of aging population, Japan renames HCAP to nursing and healthcare-associated pneumonia (NHCAP), which still falls in the scope of HAP[4].

Evidence from evidence-based medicine in recent years has further confirmed that HAP and VAP are significantly different in empirical treatment and clinical prognosis, including severity of disease, types of infectious pathogens, empirical drug selection, and drug resistance, etc. Therefore, the HAP/VAP Guideline (2016 Edition) in the United States firstly distinguishes HAP from VAP and considers them as two completely independent groups [3]. However, the guidelines in China, Japan and Europe still classify VAP as a sub-type of HAP[1][4][5].


Q2: What are the common pathogens of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) in China?

HAP and VAP pathogens differ greatly across countries. The distribution of common pathogens and their drug resistance characteristics vary with countries, patient populations, and exposure to antibacterial drugs. However, in general, the proportion of drug-resistant gram-negative bacteria in VAP is higher than that in HAP.

In China, Acinetobacter baumannii (A. baumanii) account for a very high proportion of HAP pathogens, while Pseudomonas aeruginosa (P.aeruginosa) in European and the United States are the most predominant HAP pathogen. According to a large-scale survey results of pathogens isolated from HAP specimens in China in 2018, A. baumanii ranked the first, accounting for 16%~36%; P. aeruginosa accounted for 17%~22%, and Staphylococcus aureus (S. aureus) accounted for 9%~16%, Klebsiella pneumoniae (K.pneumoniae) accounted for 8%~15% [1]. S. aureus accounts for a similar proportion in secondary and tertiary hospitals, while Escherichia coli(E. coli), K.pneumoniae, Streptococcus pneumoniae(S. pneumoniae), and Haemophilus influenzae(H. influenzae) account for a higher proportion in secondary hospitals than tertiary hospitals; among non-fermentative bacteria, P. aeruginosa accounts for a higher proportion in secondary hospitals than tertiary hospitals, while A. baumanii accounts for a slightly lower proportion in secondary hospitals than tertiary hospitals [6][7].

In the pathogenic spectrum of VAP in China, A. baumanii has an isolation rate as high as 36%~50% (the actual infection rate may not be so high), followed by P. aeruginosa and S. aureus, with comparable proportions (28%, 22% respectively). VAP is mainly found in tertiary hospitals. P. aeruginosa has a higher isolation rate in elderly patients (≥65 years) than in other populations[1].

Other common pathogens include: E. coli, Enterobacter cloacae (E. cloacae), and Stenotrophomonas maltophilia (S. maltophilia).


Q3: What about drug resistance of common pathogens in hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) in China?

The common drug-resistant bacteria in clinic include carbapenem-resistant A. baumanii (CRAB), carbapenem-resistant P. aeruginosa (CRPA), extended-spectrum β-lactamase (ESBLs) producing enterobacteriaceae bacteria, methicillin-resistant S. aureus (MRSA), and carbapenem-resistant enterobacteriaceae (CRE), etc. The key drug-resistant bacteria mainly include four negative bacteria (E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa) and one positive bacteria (MRSA).

In general, VAP has higher isolation rate of drug-resistant bacteria than HAP, and has even higher isolation rate of drug-resistant bacteria among non-fermentative bacteria. 2018 China HAP/VAP Guideline and the 2019 China surveillance network for bacterial resistance (CHINET) are used to analyze the isolation rate of drug-resistant bacteria. The 2018 guideline data mainly include HAP, while 2019 CHINET includes all specimens, dominated by respiratory tract specimens [1][8] (hereinafter referred to as the Guideline and CHINET).

CRAB has an isolation rate of 60%~70% according to the Guideline, while the rate in CHINET is as high as 79%. CRPA isolation rate is decreasing year by year, which is 20%~40% in 2018 Guideline, but as low as 23.5% in CHINET. ESBLs-producing bacteria mainly include Enterobacteriaceae bacteria, including ESBLs-Ecoli and ESBLs-KP. ESBLs-Ecoli has an isolation rate of 45%~60% and 57% in the Guideline and CHINET, respectively, which is relatively close. However, the ESBLs-KP is 25%~35% in the Guideline and as high as 46% in CHINET. MRSA has an isolation rate of 35%~40% and 31.4% in the 2018 Guideline and CHINET, respectively. The Carbapenem-resistant E. coli (CR-Ecoli) and K. pneumoniae(CRKP) is 5%~18% in the Guideline, but up to 27% in CHINET[1][8].

In view of the current drug resistance of common pathogens, the Guideline recommends highly sensitive drugs accordingly. For P. aeruginosa, the 2018 Guideline recommends polymyxins, aminoglycosides (such as amikacin), third- and fourth-generation cephalosporins (ceftazidime and cefepime), and enzyme inhibitor compound (piperacillin/tazobactam and cefoperazone/sulbactam), quinolones (levofloxacin and ciprofloxacin), carbapenems (meropenem and imipenem). Polymyxin has the lowest resistance rate of less than 1%, followed by 5% of aminoglycosides, but aminoglycosides monotherapy is not recommended, which should be combined with other drugs during treatment. Other recommended drugs have similar resistance rate. With a resistance rate of 19%, levofloxacin is a preferred drug for P. aeruginosa [1][8].

For E. coli and K. pneumoniae, the recommended therapeutic drugs are carbapenems (sensitivity rate at 82%~98%), enzyme inhibitor compound (sensitivity rate at 80%~96%), and aminoglycosides (sensitivity rate at 90%~97%). For E. coli, carbapenems (resistance rate less than 3%) and enzyme inhibitor compound (resistance rate less than 6%) are suitable choices; for K. pneumoniae, carbapenems (resistance rate 20%~26%), enzyme inhibitor compound (resistance rate 29%~32%), and levofloxacin (resistance rate 33.4%) have relatively high resistance rates, while polymyxin and tigecycline have relatively low resistance rates [1][8].

For S. maltophilia, high-sensitivity drugs include tetracyclines (minocyline, 81%~94%), quinolones (levofloxacin, 76%~90%), and sulfonamides (sulfamethoxazole/ trimethoprim, 67%~92%). CHINET monitoring also found that minocycline had the highest sensitivity rate (93.9%), followed by levofloxacin (83.8%) and sulfonamides (91.4%)[1][8].


Q4.What are the general principles in empirical antibacterial treatment for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) in China?

Firstly, the timing of anti-infection treatment: After HAP/VAP is clinically diagnosed, specimens should be collected immediately for pathogenic examination, and empirical anti-infection treatment should be timely started. Secondly, correct assessment of risk factors in multidrug-resistant (MDR) bacterial infection: For example, whether intravenous antibiotics are used within 90 days is a recognized risk factor. Thirdly, comprehensively evaluate severity of the patient’s condition, epidemiology and drug resistance of the pathogens in the medical institution, and risk factors for drug resistance in the patient before selection of appropriate drugs. Fourthly, when multiple drugs are available, choice should be made by comprehensively considering the patient’s clinical characteristics, underlying diseases, organ function status, infection site, PK/PD profile of the drug, previous medication status, and history of drug allergy, etc.[1].

For non-VAP patients, drug regimens can be recommended accordingly based on different disease severity and drug resistance risks. For non-severe patients, such as those with low risk of MDR infection, monotherapy covering P. aeruginosa should be selected as far as possible, including penicillins (piperacillin, etc.), β-lactamase inhibitor compound (piperacillin/tazobactam, cefoperazone/sulbactam, etc.), third-generation cephalosporins (cefotaxime, ceftriaxone, etc.), fourth-generation cephalosporins (cefepime, etc.), quinolones (ciprofloxacin, levofloxacin, etc.), oxacephem (latamoxef). For non-severe patients with high drug resistance risk, monotherapy or combined therapy can be selected according to the level of risk. β-lactamase inhibitor compound, third and fourth-generation cephalosporins, carbapenems combined with quinolones or aminoglycosides (amikacin) can be selected; glycopeptides or linezolid can be used in combination if there is a risk of MRSA infection. For critically ill patients, combined therapy should be selected at the beginning, such as β-lactamase inhibitor compound, carbapenem drugs combined with quinolones (such as levofloxacin), aminoglycosides; when there is risk of extensively drug-resistant (XDR) negative bacteria infection, polymyxin and tigecycline can be used in combination, while glycopeptides or linezolid can be used in combination when there is a risk of MRSA infection [1].

For VAP, there are different drug regimens based on risk factors for drug resistance. For those at low risk of MDR infection, both monotherapy and combined therapy are applicable. It is possible to select Penicillins, third- and fourth-generation cephalosporins, β-lactamase inhibitor compound, carbapenems, and quinolones (such as ciprofloxacin, levofloxacin), aminoglycosides (only for combined therapy, not monotherapy). For those at high risk of MDR infection, β-lactam drugs combined with non-β-lactams can be selected for treatment, including β-lactam enzyme inhibitor compound, third and fourth-generation cephalosporins, aztreonam, carbapenems, quinolones (such as levofloxacin), aminoglycosides. Polymyxin and tigecycline can be used in combination when there is a risk of XDR negative bacterial infection, while glycopeptides and linezolid can be used in combination when there is a risk of MRSA infection[1].

Therefore, levofloxacin plays an important role in the treatment of HAP and VAP.


Q5: What role does levofloxacin play in treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP)?

A: Firstly, levofloxacin has a broad antibacterial spectrum. Levofloxacin is a third-generation quinolone drug. Compared with the first and second generation drugs, levofloxacin retains favorable antibacterial activity against gram negative bacteria and gram positive bacteria other than MRSA (such as S. pneumoniae, enterococci). Secondly, levofloxacin has a high concentration in lung tissue and can cover common pathogens (S. pneumoniae and H. influenzae) and atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila) that cause CAP, which also has favorable antibacterial activity against penicillin-resistant S. pneumoniae (PRSP). Therefore, levofloxacin is also a proven respiratory quinolone drug in clinical practice. In addition, levofloxacin has a favorable anti-Pseudomonas effect. It is recommended to use alone or in combination with other anti-Pseudomonas drugs to effectively fight P. aeruginosaj, the main pathogen of HAP. Also, it has certain antibacterial activity against A. baumanii, K. pneumoniaand and S. maltophilia [9].

Chinese Guideline recommends quinolones as monotherapy or combined therapy drug, and emphasizes the use of quinolones with anti-P. aeruginosa effect (only levofloxacin and ciprofloxacin), but does not recommend aminoglycosides for monotherapy[1].

All foreign HAP/VAP guidelines (American IDSA/ATS, European ERS, Japanese JSR) emphasize the need to cover P. aeruginosa in empirical treatment, and recommend levofloxacin for monotherapy or combined therapy. The guidelines recommend levofloxacin therapy for across HAP patients, including those without high risk of death or risk of MRSA; those without high risk of death, but with MRSA risk; those with high risk of death or intravenously administered with antibacterial agents within 90 days. The guidelines also recommend levofloxacin treatment for VAP patients demanding MSSA coverage or suspected to require empirical coverage of P. aeruginosa[3][4][5]. Levofloxacin in combination with imipenem or polymyxin can create synergistic effect in the treatment of MDR acinetobacter and P. aeruginosa[10]. Narrowed selection window for resistance mutations in A. baumannii can be observed in combination with levofloxacin[11].

The recommended levofloxacin dosage and treatment cycle for HAP/VAP are different at home and abroad. The recommended dose in foreign guidelines is 750mg/d[3]. The maximum dose for severely drug-resistant bacteria can be increased to 500 mg, bid. The recommended dose in Chinese Guideline is 500mg/d[1]. The treatment cycle should be adjusted for different pathogens. In general, 7~14 days is sufficient for enterobacteriaceae infection. The treatment cycle should be longer for non-fermentative bacteria, requiring 14~21 days. After receiving the appropriate initial therapy, those with favorable clinical response can have treatment cycle shortened from the regular duration to a minimum of 7 days [2].


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