Since the 1990s, multi-drug resistant (MDR) non-fermentative gram-negative bacilli (Non-Fermentative Gram-Negative Bacteria, hereinafter referred to as “non-fermentative bacteria”) have become important pathogens of hospital infections and are rapidly increasing. Non-fermentative bacteria are a large group of Gram-negative bacilli that cannot use or can only oxidize and use glucose (non-glucose fermenting), aerobic or partly anaerobic, mainly including Pseudomonas aeruginosa, Acinetobacter, Maltophilus, Burkholderia cepacia and Bacillus faecalis, etc. Among them Pseudomonas aeruginosa and Acinetobacter spp. (80%-90% of Acinetobacter baumannii) are of particular concern because of their strong environmental adaptability and high drug resistance and dissemination, making them the “superbugs” of hospital infections and should be taken seriously by clinicians [1,2].
1. Epidemiology of non-fermentative bacterial infections
In recent years, the epidemiological characteristics of non-fermentative bacterial infections have been highlighted in two aspects: first, the increasing incidence of nosocomial infections, especially pulmonary infections. The Clinical Isolates Resistance Surveillance (CHINET) of hospitals in 14 different regions of China showed that the proportion of Pseudomonas aeruginosa and Bacillus spp. to Gram-negative bacteria is increasing year by year, reaching 14.8% for P. aeruginosa and 16.1% for B. immobilis in 2010 [3]. The results of a recent clinical survey of hospital-acquired pneumonia (HAP) in 16 large teaching hospitals in China showed that the isolation rates of P. aeruginosa and Fusobacterium spp. were 20.9% and 29.2%, respectively, occupying the top two positions and exceeding 50% of the total isolation rate of pathogenic bacteria, and it is thought-provoking that this increase occurred at a time when people have made great progress in the diagnosis, treatment and prevention of HAP. Secondly, there is an increasing rate of drug resistance in non-fermentative bacteria, especially Pseudomonas aeruginosa and Fusobacterium spp. The global bacterial resistance surveillance data (SENTRY) shows that non-fermentative bacteria occupy the top positions among HAP pathogens, accompanied by a yearly increase in resistance to commonly used antimicrobial drugs [4]. CHINET 2010 surveillance data in China showed that the resistance rates of Pseudomonas aeruginosa and Meropenem were 30.8% and 25.8%, respectively, while the resistance rates of Bacillus spp. (89.6% for Acinetobacter baumannii) were as high as 57.1% and 58.3%, with a significant increase in the number of pan-drug resistant (PDR) strains (1.7% for P. aeruginosa and 21.4% for Bacillus spp. 21.4%), especially the increase of drug resistance in immobile bacilli spp. was more significant [3]. This is more prominent in respiratory infections, as clinical surveys of HAP in China showed resistance rates of 70.7% and 48.8% for Pseudomonas aeruginosa and 48.8% for Meropenem, and 78.9% and 76.8% for Acinetobacter baumannii.
Non-fermentative pulmonary infections have their own relatively specific clinical features. Most of them have susceptibility factors, such as long-term ICU admission, mechanical ventilation, tracheotomy, indwelling central venous catheter, long-term use of triple cephalosporins or carbapenem antibiotics, being in the same ward with patients already infected with non-fermentative bacteria, and negligence of staff in environmental and hand cleaning. In addition to these high-risk factors, Pseudomonas aeruginosa infections are also relatively common in immunocompromised patients such as neutrophil deficiency, after glucocorticoid therapy and chemotherapy for solid tumors [5], while infections with Fusobacterium spp. are more common in patients with pre-existing respiratory colonization and long-term mechanical ventilation [6].
2. diagnosis of non-fermentative bacterial pulmonary infections
Because colonization of the respiratory tract by non-fermentative bacteria is extremely common, the greatest clinical confusion regarding non-fermentative pulmonary infections is currently a diagnostic problem: how should non-fermentative bacteria isolated from sputum or transtracheal aspiration (TTA) specimens be distinguished as colonized or infected? The distinction between colonization and infection is very important for the rational use of antibiotics, otherwise it is very likely to lead to under- or over-treatment, but this is precisely the challenge that has not been solved in the clinical setting of respiratory tract infection so far. As far as the current level of knowledge is concerned, it can be addressed in two ways. First, when collecting respiratory specimens clinically, patients should be adequately trained, and bronchoscopic anti-pollution brush sampling should be used when necessary to maximize the quality of respiratory secretion specimens. The clinical microbiology laboratory should strictly grasp the quality of sputum specimens. Gram staining microscopy should be performed before sputum specimen inoculation to determine whether the sputum specimen is qualified, and attention should be paid to the presence of leukocyte phagocytosis or concomitant lineage phenomenon and bacterial staining and morphology. The semi-quantitative and quantitative bacterial culture of respiratory specimens can provide important reference values for clinical purposes. Second, the need for antibiotic therapy in patients with non-fermentative bacteria isolated from respiratory specimens should refer to the following: (i) clinical signs, symptoms and imaging of new, or persistent, or exacerbated pulmonary exudates, infiltrates, or solid lesions consistent with pneumonia; (ii) host factors such as underlying disease, immune status, prior antibiotic therapy, and other risk factors associated with morbidity such as duration of mechanical ventilation; and (iii) Patients being treated with antibiotics who once improved and then worsened, in time to match the appearance of non-fermenting bacteria and to exclude other infections such as sinusitis, urinary tract infections or catheter-related infections; ④ Evaluate the clinical significance of positive culture results in terms of specimen collection method, specimen quality, bacterial concentration (quantitative or semi-quantitative culture), and what is seen in the smear. ⑤ Clinical evidence of pulmonary infection exists with multiple sputum cultures suggestive of pure Pseudomonas aeruginosa or Acinetobacter baumannii growth [1].
3. Treatment of non-fermentative bacterial lung infections
Due to the increasing bacterial resistance, another clinical confusion regarding non-fermentative bacterial lung infections is the treatment issue: how should antibiotic therapy be selected in the face of severe drug resistance? The drugs once applied to the treatment of non-fermentative bacterial infections include anti-Pseudomonas penicillins and cephalosporins, aminotrans, aminoglycosides, fluoroquinolones, carbapenems, etc. Especially carbapenems used to be very important and effective drugs for the treatment of non-fermentative bacterial infections. However, in recent years, due to the rapid increase in drug resistance of non-fermentative bacteria, and resistance to most other antibiotics at the same time, resulting in an increasing number of severely drug-resistant (XDR) and even PDR strains, so that the application of sensitive drugs is very limited, the current recommended therapeutic drugs Pseudomonas aeruginosa only polymyxin, new carbapenems such as Biapenem and Doripenem, and Acinetobacter baumannii only sulbactam, polymyxin, tigecycline. The only other species in A. baumannii were sulbactam, polymyxin and tigecycline. Therefore, the clinical treatment of MDR non-fermentative pneumonia is very difficult and most advocate the use of antibiotic combinations, based on carbapenems, sulbactam and polymyxin respectively, combined with different combinations of quinolones, aminoglycosides, minocycline, tigecycline, rifampin, macrolides. In vitro antimicrobial studies have shown different degrees of synergistic effects of combination therapy, such as carbapenems (imipenem) in combination with amikacin or isopamicin in vitro against MDR Pseudomonas aeruginosa 4.0% showed synergy and 46.0% partial synergy [7], while carbapenems (meropenem) in combination with sulbactam in vitro against carbapenem-resistant Acinetobacter baumannii 29.2% showed synergy , 47.9% partially synergistic and 10.5% additive [8]. The dose of sulbactam should be appropriately increased if applied for the treatment of non-fermentative bacillus spp. infections, and 6.0-8.0/d (in 3-4 doses) is advocated abroad. The principles of treatment of comprehensive non-fermentative antibiotics: ① adhere to targeted therapy, use the necessary empirical treatment in selective cases, and select sensitive antibacterial drugs according to the drug sensitivity results as far as possible; ② for Pseudomonas aeruginosa infection recommended combination therapy to anti-Pseudomonas β-lactams combined with anti-Pseudomonas quinolones or aminoglycosides, for carbapenem-resistant especially PDR P. aeruginosa infection For carbapenem-resistant Pseudomonas aeruginosa infections, especially PDR, polymyxin-based combination therapy is recommended, and polymyxin and aminoglycosides can be applied by nebulized inhalation simultaneously; (3) for carbapenem-sensitive Fusobacterium spp. (4) Optimize the dosing regimen and route of administration according to the principles of antibiotic PK/PD, e.g., β-lactams should be given more frequently and for longer periods, and usually require the use of larger doses and longer courses of therapy [1,9].
4. Prevention of non-fermentative bacterial lung infections
It is important to note that anti-infective therapy may be temporarily unnecessary if only the isolated culture of respiratory secretions is positive for non-fermentative bacteria without clinical symptoms or imaging evidence. Patients with mechanical ventilation should be extubated as soon as possible if their condition allows, and if necessary, they can use a noninvasive ventilator to assist in breathing. On the other hand, prevention is easily overlooked in clinical practice. The most important measures to control non-fermentative pneumonia are good antibiotic stewardship and prevention of outbreaks of non-fermentative bacteria in healthcare facilities. For example, the development of antibiotic treatment guidelines and antibiotic rotation strategies; prevention of contamination of humidifiers, aspirators and furniture, blood pressure cuffs, attention to hand hygiene of medical staff, bedside isolation and disinfection of susceptible patients, oral hygiene, and cleanliness during medical invasive operations [1].
References
1. Shi Y. Correct response to Bacillus immobilis pulmonary infection. Chinese Journal of Respiratory and Critical Care,2012,11:13-14.
2. Fujitani S, Sun HY, Yu VL, et al. Pneumonia due to Pseudomonas
aeruginosa: Part I: epidemiology, clinical diagnosis, and source.
Chest,2011,139:909-919.
3. Wang F, Zhu D-M, Hu F-P, et al. 2010 China CHINET bacterial resistance surveillance. Chinese Journal of Infection and Chemotherapy,2011,11:321-332.
4. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia
and ventilator-associated bacterial pneumonia,
2010,51(S1):S81-S87.
5. Tumbarello M, Repetto E, Trecarichi EM, et al. Multidrug-resistant
Pseudomonas aeruginosa bloodstream infections: risk factors and mortality.
Epidemiol Infect,2011,139:1740-1749.
6. Anunnatsiri S, Tonsawan P. Risk factors and clinical outcomes of
multidrug-resistant Acinetobacter baumannii bacteremia at a university hospital
Southeast Asian J Trop Med Public Health, 2011,42:693-703.
7. Song W, Woo HJ, Kim JS, et al. In vitro activity of beta-lactams in
combination with other antimicrobial agents against resistant strains of
Pseudomonas aeruginosa. Int J Antimicrob Agents, 2003,21:8-12.
8. Kiffera CRV, Jorge LM, Sampaioa JLM, et al. In vitro synergy test of
meropenem and sulbactam against clinical isolates of Acinetobacter baumannii.
Diag Microbiol Infect Dis,2005,52:317-332.
9. Arnold HM, Sawyer AM, Kollef MH. Use of adjunctive aerosolized
antimicrobial therapy in the treatment of pseudomonas aeruginosa and
Respiratory Care.
Articles in Press. Published on February 17, 2012 as DOI:
10.4187/respcare.01556.