Outcomes and prognostic factors of tigecycline treatment for hospital-acquired pneumonia involving multidrug-resistant Acinetobacter baumannii

Abstract

Objective: To compare outcomes and prognostic factors of tigecycline (TC)-based treatment with those of other antibiotic-based treatments in the treatment of hospital-acquired pneumonia caused by multidrug-resistant Acinetobacter baumannii (MDRAB).

Methods: A retrospective analysis of data was performed from all patients ≥18 years who were treated in the ICU at Xiangya Hospital, Changsha, China (January 2016 to June 2017) with hospital-acquired pneumonia involving monomicrobial MDRAB. Patients were separated into TC and non-TC groups.

Results: Of 86 MDRAB-positive patients, 59 were in the TC group and 27 were in the non-TC group. The 28-day death rates were not significantly different between the two groups, but the TC group had significantly more patients with a good clinical prognosis than the non-TC group. Although prognostic markers for a poor clinical response were sepsis, procalcitonin concentration and APACHE II scores, TC therapy was found to be a protective factor.

Conclusions: TC based therapy was associated with a positive clinical response in the treatment of MDRAB caused hospital-acquired pneumonia. Further studies are required to confirm our results.

Keywords

Tigecycline multidrug-resistance Acinetobacter baumannii hospital-acquired pneumonia

Introduction

Pneumonia caused by multidrug-resistant Acinetobacter baumannii (MDRAB) often leads to prolonged hospitalization, increased treatment costs and high death rates.^1–3 Moreover, hospital-acquired A. baumannii infection rates have increased rapidly in recent years, particularly in intensive care units (ICU), possibly because of the high prevalence of MDRAB strains.^1,4–7

Tigecycline (TC) is a glycylcycline antibiotic developed to address the globally emerging crisis of antibiotic resistance; it was first approved for clinical use in 2005.^8,9 Although clinical data on TC are sparse and its effects are often modified by other concurrently used antibiotics,^10–12 in vitro analyses have shown that TC has antibacterial activity against A. baumannii.^13–15 Susceptibility testing has also demonstrated that TC can be used for the treatment of drug-resistant bacteria.^16, Indeed, some retrospective studies involving small sample sizes have shown that TC is effective in MDRAB nosocomial and hospital acquired pneumonia.^16,17 However, studies comparing the clinical efficacy of TC with other antibiotics in the treatment of MDRAB infection in patients with hospital-acquired pneumonia are few and prognostic indicators have not been defined.

The aim of this retrospective study was to evaluate outcomes and prognostic risk factors of TC-based treatment by comparison with those of other antibiotic-based treatments in the treatment of hospital-acquired pneumonia caused by MDRAB.

Patients and methods

This retrospective study included all patients ≥18 years who were consecutively admitted to the ICU at Xiangya Hospital, Central South University, Changsha, China between January 2016 and June 2017 with hospital-acquired pneumonia involving monomicrobial MDRAB. Patient data were collected from the hospital’s electronic medical records system. The study was approved by the Ethics committee of Xiangya Hospital, Central South University and because of the study’s retrospective design, there was no requirement for patients’ informed consent.

Hospital-acquired pneumonia was defined as pneumonia that occurred 48 h or more after admission.^18,19 MDRAB was defined as the A. baumannii isolate was resistant to representative antibiotics from at least three different classes of antimicrobial agents such as aminoglycosides, β-lactams, quinolones, and/or tetracyclines.¹⁹

Depending on their antibiotic treatment, patients were separated into a ‘TG’ and a ‘non-TG’ group. Patients in the TG group had received TG alone or in combination with other antibiotics. TG had been administered for five days with a 100 mg IV loading dose followed by 50 mg IV every 12 h. Patients in the non-TG group had received carbapenem-based (i.e., imipenem-cilastatin, 500mg IV every 6 h or meropenem, 1 g IV every 8 h) and/or cefoperazone/sulbactam-based (i.e., 3g IV every 8 h for at least five days) regimens.

Baseline demographic data, laboratory test results, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores,²⁰ Glasgow Coma Scale (GCS) scores²¹ and presence of sepsis were recorded. The diagnosis of sepsis had been made according to established criteria.²² Other risk factors recorded were: antibiotic use in the previous three months; bedsores; mechanical ventilation, urethral and/or deep vein catheterisation; immunosuppressive drug use; sepsis; primary infection site; mixed infections; treatment details; length of hospitalization; ICU duration; death; microbial and clinical outcomes.

Clinical prognosis at the end of treatment was defined as good (complete or partial resolution of symptoms/signs of infection) or poor (no improvement or deterioration of signs/symptoms of infection). Primary bacteraemia was defined as bacteraemia associated with catheter-related infections, whereas secondary bacteraemia was defined as bacteraemia that developed subsequent to the primary infection.²³

Statistical analyses

Data were analysed using the Statistical Package for Social Sciences (SPSS®) for Windows® release 22.0 (IBM Corp., Armonk, NY, USA). All tests were two-sided and a P-value <0.05 was considered to indicate statistical significance. Quantitative data were expressed as median and interquartile range and were analysed using the Mann-Whitney test. Numerical data were expressed as a percentage and were analysed using the χ² test. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated for all potential risk factors for poor prognosis. All variables were included in the univariate analysis and those with a P value of 0.05 were included in a logistic regression model for multivariate analysis.

Results

Of the 86 MDRAB-positive patients with hospital-acquired pneumonia that were identified for the study, 59 were in the TC group and 27 were in the non-TC group. In terms of baseline demographic data, there were no significant differences between groups in median age, sex and concomitant diseases, apart from coronary heart disease which was significantly more prevalent in the TC group (51% vs. 26%, P = 0.03; Table 1).

Table 1.

Pre-treatment demographic characteristics of patients with hospital-acquired pneumonia involving multidrug-resistant A. baumannii.

Demographic characteristics	Total Number of patients (N = 86)	Groups		Statistical significance
Demographic characteristics	Total Number of patients (N = 86)	TC group (n = 59)	non-TC group (n = 27)	Statistical significance
Age, years	69 (59,77）	69 (59,78）	69 (59,75)	ns
Sex
Male	46 (53)	32 (54)	14 (52)	ns
Female	40 (47)	27 (46)	13 (48)
Concomitant diseases
Coronary heart disease	37 (43)	30 (51)	7 (26)	P = 0.03
Diabetes	40 (47)	29 (49)	11 (41)	ns
COPD	71 (83)	50 (85)	21 (78)	ns
Chronic kidney disease	12 (14)	6 (10)	6 (22)	ns
Malignant tumours	4 (5)	2 (4)	2 (7)	ns

Values are shown as median (interquartile range) or n (%)

TC, Tigecycline; COPD , Chronic obstructive pulmonary disease, ns, not significant.

There were also no differences between groups in baseline risk factors. These included: the proportion of patients who had used antibiotics in the previous three months; occurrence of bedsores; mechanical ventilation use (approximately 90% of patients); patients who underwent deep vein catherization; long-term immunosuppressive drug use (Table 2). However, fewer patients in the non-TC group had urethral catherization compared with the TC group (82% vs. 97%; P = 0.029).

Table 2.

Pre-treatment risk factors of patients with hospital-acquired pneumonia involving multidrug-resistant A. baumannii.

Risk Factors	Total Number of patients (N = 86)	Groups
Risk Factors	Total Number of patients (N = 86)	TC group (n = 59)	non-TC group (n = 27)	Statistical significance
Antibiotics used in previous 90 days	81 (94)	56 (95)	25 (93)	ns
Bedsores	33 (38)	22 (37)	11 (41)	ns
Invasive mechanical ventilation	77 (90)	53 (90)	24 (89)	ns
Urethral catherization	79 (92)	57 (97)	22 (82)	P = 0.029
Deep vein catheterization	32 (37)	25 (42)	7 (26)	ns
Long-term immunosuppressives	7 (8)	4 (7)	3 (11)	ns

Values are shown n (%)

TC, Tigecycline, ns, not significant.

Although there were no significant differences between the two groups in the incidence of fever, disease severity (i.e., APACHE II and GCS scores) and most baseline laboratory measures, patients in the non-TC group had higher median serum creatinine levels compared with the TC group (86 vs 68 µmol/l, P = 0.032; Table 3). Furthermore, sepsis was more common in the TC group than the non-TC group (61% vs. 22%, P = 0.001).

Table 3.

Pre-treatment clinical characteristics of patients with hospital-acquired pneumonia involving multidrug-resistant A. baumannii.

Clinical characteristics	Total Number of patients (N = 86)	Groups		Statistical significance
Clinical characteristics	Total Number of patients (N = 86)	TC group (n = 59)	non-TC group (n = 27)	Statistical significance
Fever（>38.5°C）	48 (56)	29 (51)	19 (70)	P = 0.066
Laboratory measures
White blood cells, × 10⁹/l	11.6 (10.3,14.5)	11.6 (10.4,14.6)	11.0 (9.9,14.4)	ns
C-reactive protein, mg/l	47.5 (28, 73)	49 (29,76)	47 (26, 66)	ns
Procalcitonin, ng/ml	0.7 (0.4, 2.9)	0.7 (0.4, 2.4)	0.9 (0.3, 4.1)	ns
Serum albumin, g/l	28.8 (23.9, 34.0)	29.1 (23.9, 33.8)	27.9 (22.8, 34.8)	ns
Blood urea nitrogen, mmol/l	7.8 (6.4, 11.1)	7.9 (6.5, 10.7)	7.8 (5.7, 12.3)	ns
Serum creatinine, µmol/l	76 (62, 101)	68 (60, 97)	86 (68, 118)	P = 0.032
Disease severity
Sepsis	43 (49)	36 (61)	6 (22)	P = 0.001
GCS score	11 (8, 13)	11 (9, 13)	11 (8, 14)	ns
APACHE II score	15 (11, 19)	15 (11, 20)	13 (10, 18)	ns

Values are shown as median (interquartile range) or n (%)

TC, Tigecycline, GCS, Glasgow Coma score; APACHE II score, acute physiology and chronic health evaluation II score, ns, not significant.

Pre-treatment microbial records showed that the respiratory tract was the most common site of primary infections in both groups (Table 4). However, primary bacteraemia (defined as catheter related) was more common in the TC group compared with the non-TC group (29% vs. 7%). In addition, co-infection with other bacteria or fungi was present in most patients from both groups. Patients in the TC group showed a higher prevalence of Candida albicans co-infection and patients in the non-TC group patients had a higher prevalence of Pseudomona aeruginosa co-infection (P = 0.026) (Table 4).

Table 4.

Pre-treatment microbial characteristics of patients with hospital-acquired pneumonia involving multidrug-resistant A. baumannii.

Microbial characteristics	Total Numberof patients (N = 86)	Groups		Statistical significance
Microbial characteristics	Total Numberof patients (N = 86)	TC group (n = 59)	non-TC group (n = 27)	Statistical significance
Primary infection site
Catheter-related	19 (22)	17 (29)	2 (7)	P = 0.049
Respiratory tract	58 (67)	35 (59)	23 (85)
Other	9 (11)	7 (12)	2 (7)
Mixed infections
Candida albicans	34 (40)	29 (49)	5 (19)	P = 0.026
Pseudomonas aeruginosa	31 (36)	18 (31)	13 (48)
Other	21 (24)	12 (20)	9 (33)

Values are shown as n (%)

TC, Tigecycline.

In terms of outcomes following treatment of MDRAB caused hospital-acquired pneumonia, the median duration of treatment was shorter for the TC group compared with the non-TC group (12 vs. 14 days, P = 0.047) but the proportion of patients that required a change in antibiotic therapy was significantly greater in the TC group compared with the non-TC group (25 vs 9; P = 0.025; Table 5). However, there were no significant differences between groups in 28-day death rates, duration of hospital or ICU stay. For microbial outcome, the non-TC group had a higher A. baumannii clearance rate than the TC group (19% vs. 3%, P = 0.029). Nevertheless, the TC group had more patients with improved clinical symptoms than the non-TC group (73% vs. 48%, P = 0.026). Interestingly, approximately 50% of patients in each group had a poor response (Table 5).

Table 5.

Outcomes following treatment for hospital-acquired pneumonia involving multidrug-resistant A. baumannii.

Outcomes	Total Numberof patients (N = 86)	Groups		Statistical significance
Outcomes	Total Numberof patients (N = 86)	TC group (n = 59)	non-TC group (n = 27)	Statistical significance
Treatment for HAP
Antibiotic usage time^#	12 (8, 18)	12 (7, 16）	14 (11, 19）	P = 0.047
Switch to other antibiotics	34 (40)	25 (42)	9 (33)	P = 0.025
Died within 28 days	23 (27)	15 (25）	8 (30)	ns
Length of hospital stay, days	15 (12, 19)	12 (7, 18）	14 (11, 19)	ns
ICU duration, days	12 (9, 15)	12 (7, 16)	14 (11, 19)	ns
Microbial and clinical outcomes
Pathogen clearance	7 (8)	2 (3)	5 (19)	P = 0.029
Good (complete/partial response)*	56	43 (73)	13 (48)	P = 0.026
Poor (no improvement/worsened)	30	16 (48)	14 (52)	ns

Values are shown as median (interquartile range) or n (%)

^#Total duration of antibiotic use

*Improvement resulting from all antibiotics used

TC, Tigecycline; HAP, hospital-acquired pneumonia, ns, not significant.

Univariate logistic regression analysis showed that predictors of a poor clinical prognosis were procalcitonin concentration, blood urea nitrogen concentration, sepsis, and APACHE II scores. As these variables were not co-linear, a multivariate logistic regression analysis was applied to the data to determine whether they independently affected the clinical prognosis. Results showed that sepsis (OR, 8.48), increased PCT concentration (OR, 1.11), and increased APACHE II scores (OR, 1.12) were risk factors associated with a poor clinical prognosis for patients with MDRAB related hospital-acquired pneumonia. In comparison, TC therapy was a protective factor (OR = 0.08) (Table 6).

Table 6.

Univariate and multivariate analyses of predictors for a poor clinical response following antibiotic treatment of hospital-acquired pneumonia involving multidrug-resistant A. baumannii.

	Univariate analysis		Multivariate analysis
Risk Factors	Odds Ratio (95% CI)	Statistical significance	Odds Ratio (95% CI)	Statistical significance
Age	1.03 (0.99, 1.08)	ns
Sex	0.99 (0.41, 2.41)	ns
Concomitant diseases
Coronary heart disease	0.54 (0.21, 1.35)	ns
Diabetes	1.24 (0.51, 3.02)	ns
COPD	1.09 (0.33, 3.53)	ns
Chronic kidney disease	2.08 (0.61, 7.14)	ns
Malignant tumours	1.93 (0.26, 14.43）	ns
Duration of the antibiotics	1.00 (0.93, 1.08)	ns
Duration of hospital stay	0.99 (0.88, 1.05)	ns
Duration of ICU stay	0.93 (0.84, 1.03)	ns
Pre-treatment risk factors
Antibiotics used in previous 90 days	0.79 (0.13, 5.02)	ns
Bedsores	0.45 (0.17, 1.18))	ns
Mechanical ventilation	2.00 (0.39, 10.30)	ns
Urethral catherization	0.69 (0.14, 3.32)	ns
Deep vein catheterization	0.49 (0.18, 1.28)	ns
Long-term immunosuppressive	0.28 (0.03, 2.51)	ns
Fever（>38.5°C）	2.51 (0.98, 6.42)	ns
Laboratory tests
White blood cell count	0.91 (0.79, 1.05)	ns
C-reactive protein	1.01 (1.00, 1.03)	ns
Procalcitonin	1.10 (1.01, 1.20)	0.024	1.11 (1.00, 1.22)	P = 0.049
Serum albumin	1.04 (0.96, 1.11)	ns
Blood urea nitrogen	1.12 (1.01, 1.24)	0.034	1.11 (0.90, 1.25)
Serum creatinine	1.01 (1.00, 1.02)	ns
Severity
Sepsis	3.09 (1.22, 7.83)	0.017	8.48 (1.71, 42.00)	P = 0.009
GCS score	0.88 (0.76,1.02)	ns
APACHE II score	1.08 (1.01, 1.17)	0.037	1.12 (1.03, 1.23)	P = 0.011
Primary infection site
Catheter-related	1.62 (0.26, 10.23)	ns
Respiratory tract	2.14 (0.41, 11.23)	ns
Other
Mixed infections
Candida albicans	0.78 (0.25, 2.42)	ns
Pseudomonas aeruginosa	0.89 (0.28, 2.82)	ns
Treatment for MDRAB caused HAP
Tigecycline	0.35 (0.13, 0.89)	0.028	0.08 (0.02, 0.43)	P = 0.03
Antibiotics switch	0.83 (0.33, 2.07)	ns
Pathogen clearance	0.29 (0.03, 2.51)	ns

TC, Tigecycline; COPD, Chronic obstructive pulmonary disease; ICU, intensive care unit; GCS, Glasgow Coma score; APACHE II score, acute physiology and chronic health evaluation II score; HAP, hospital-acquired pneumonia; MDRAB, multidrug-resistant Acinetobacter baumannii, ns, not significant.

Discussion

A. baumannii is a non-fermenting, gram-negative bacillus that is widely distributed in the hospital environment and can survive on artificial surfaces for long periods.²⁴ Accordingly, the pathogen is responsible for a significant percentage of hospital-acquired infections.²⁴ Strains of A. baumannii often display high levels of drug resistance, achieved via the expression of antibiotic-inactivating enzymes and mutation of antibiotic targets, which present a significant challenge for the control and treatment of this pathogen.²⁴ Although immunotherapy-based treatments for A. baumannii infection have shown promising activity,^25,26 their potential therapeutic use remains to be determined. Treatment of A. baumannii infections typically include control measures aimed at reducing the invasive spread of infection. The antibiotic, TC has been shown to have activity against multidrug-resistant Acinetobacter species.²⁷ Moreover, a study from nine cities in China demonstrated that a majority of A. baumannii isolates were susceptible to TC.²⁸ However, while some studies have found that TC can be used successfully in hospital hospital-acquired pneumonia caused by MDRAB infection,²⁹ others have found that the clinical outcomes following TC treatment were suboptimal.¹⁷ In addition, controversy exists regarding all-cause mortality rates and tissue concentration levels associated with TC.^30,31

The findings of this retrospective review of cases showed that while the 28-day death rates, length of ICU and hospital stay were not significantly different between the two groups, the TC group had a better long-term clinical prognosis compared with the non-TC group. Nevertheless, the non-TC group showed a higher pathogen clearance rate compared with the TC group. Interestingly, significantly more patients in the TC group than in the non-TC group had switched their antibiotics. The observed lack of efficacy of TC in this current study may have been influenced by the fact that the majority of patients were in the terminal stages of severe infection prior to the administration of TC, and that TC was most likely used as a last-line antibiotic. We speculate that an increased dose of TC may have increased its efficacy, which is supported by the findings of a study in patients with ventilator-associated pneumonia who tended to have better clinical outcome if they were treated with a high-dose regimen of TC.⁹

Although there were no differences between groups in procalcitonin levels and APACHE II scores, multivariate analysis showed that both these factors were prognostic markers for a poor clinical response. In addition, sepsis, which was more common in the TC group, and TC treatment were also prognostic markers for a poor clinical response in hospital-acquired pneumonia caused by MDRAB. Interestingly, antibiotic switch and pathogen clearance were non-significant prognostic factors

Further studies are required to evaluate our findings which were probably influenced by the retrospective design of the study based on information from patients who were receiving multidrug based TC regimens. Other limitations of our study included its small sample size, single centre design and the imbalance in study group numbers; more than twice as many patients were in the TC group compared with the non-TC group. More multicentre, prospective, controlled studies involving large number of patients are needed to examine the long-term efficacy and safety of TC for the treatment of hospital-acquired pneumonia caused by MDRAB.

In summary, our results show that TC based therapy was associated with a positive clinical response in the treatment of MDRAB caused hospital-acquired pneumonia and should perhaps be considered for use in severe cases as a last-line antibiotic as part of combination therapy.

Footnotes

Acknowledgements

We thank Tamsin Sheen, PhD, from Liwen Bianji, for editing the manuscript.

Declaration of conflicting interests

The authors declare that there are no conflicts of interest.

Funding

Project Supported by National Key R&D Program of China (2018YFC1311900) and National Natural Science Foundation of China (81770080).

ORCID iD

Ben Liu

References

Potron

Poirel

Nordmann

Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: mechanisms and epidemiology.

Int J Antimicrob Agents 2015; 45: 568–585.

Antunes

Visca

Towner

KJ.

Acinetobacter baumannii: evolution of a global pathogen.

Pathog Dis 2014; 71: 292–301.

Yang

Liu

, et al. Detection of the plasmid-mediated quinolone resistance determinants in clinical isolates of Acinetobacter baumannii in China. J Chemother 2016; 28: 443–445.

Salgado

O’Grady

Farr

BM.

Prevention and control of antimicrobial-resistant infections in intensive care patients.

Crit Care Med 2005; 33: 2373–2382.

Qureshi

Hittle

O'Hara

, et al. Colistin-resistant Acinetobacter baumannii: beyond carbapenem resistance. Clin Infect Dis 2015; 60: 1295–1303.

Zilberberg

Kollef

Shorr

AF.

Secular trends in Acinetobacter baumannii resistance in respiratory and blood stream specimens in the United States, 2003 to 2012: a survey study.

J Hosp Med 2016; 11: 21–26.

Al-Gethamy

Faidah

Adetunji

, et al. Risk factors associated with multi-drug-resistant Acinetobacter baumannii nosocomial infections at a tertiary care hospital in Makkah, Saudi Arabia - a matched case-control study. J Int Med Res 2017; 45: 1181–1189.

Doan

Fung

Mehta

, et al. Tigecycline: a glycylcycline antimicrobial agent. Clin Ther 2006; 28: 1079–1106.

De Pascale

Montini

Pennisi

, et al. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care 2014; 18: R90.

10.

Fishbain

Peleg

AY.

Treatment of Acinetobacter infections.

Clin Infect Dis 2010; 51: 79–84.

11.

Horan

Andrus

Dudeck

MA.

CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.

Am J Infect Control 2008; 36: 309–332.

12.

Amat

Gutiérrez-Pizarraya

Machuca

, et al. The combined use of tigecycline with high-dose colistin might not be associated with higher survival in critically ill patients with bacteraemia due to carbapenem-resistant Acinetobacter baumannii. Clin Microbiol Infect 2018; 24: 630–634.

13.

Garnacho-Montero

Sa-Borges

Sole-Violan

, et al. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit Care Med 2007; 35: 1888–1895.

14.

Karageorgopoulos

Kelesidis

, et al. Tigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence. Antimicrob Chemother 2008; 62: 45–55.

15.

Kim

Moon

Huh

, et al. Comparable efficacy of tigecycline versus colistin therapy for multidrug-resistant and extensively drug-resistant Acinetobacter baumannii pneumonia in critically Ill patients. PLoS One 2016; 11: e0150642.

16.

Zhou

Chen

, et al. Clinical experience with tigecycline in the treatment of hospital-acquired pneumonia caused by multidrug resistant Acinetobacter baumannii. BMC Pharmacol Toxicol 2019; 20: 19.

17.

Shin

Chang

Kim

, et al. Clinical outcomes of tigecycline in the treatment of multidrug-resistant Acinetobacter baumannii infection. Yonsei Med J 2012; 53: 974–984.

18.

Falagas

Koletsi

Bliziotis

IA.

The diversity of definitions of multidrug-resistant (MDR) and pandrug-resistant (PDR) Acinetobacter baumannii and Pseudomonas aeruginosa.

J Med Microbiol 2006; 55: 1619–1629.

19.

Magiorakos

Srinivasan

Carey

, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18: 268–281.

20.

Knaus

Draper

Wagner

, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13: 818–29.

21.

Teasdale

Jennett

Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2 (7872):81–84.

22.

Martin

Mannino

Eaton

, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348: 1546–1554.

23.

Seifert

The clinical importance of microbiological findings in the diagnosis and management of bloodstream infections.

Clin Infect Dis 2009; 48: S238–S245.

24.

Manchanda

Sanchaita

Singh

Multidrug resistant acinetobacter.

J Glob Infect Dis 2010; 2: 291–304.

25.

Tan

, et al. Small protein A and phospholipase D immunization serves a protective role in a mouse pneumonia model of Acinetobacter baumannii infection. Mol Med Rep 2017; 16: 1071–1078.

26.

Guo

Xun

Han

A bovine myeloid antimicrobial peptide (BMAP-28) and its analogs kill pan-drug-resistant Acinetobacter baumannii by interacting with outer membrane protein A (OmpA).

Medicine (Baltimore) 2018; 97: e12832.

27.

Seifert

Stefanik

Wisplinghoff

Comparative in vitro activities of tigecycline and 11 other antimicrobial agents against 215 epidemiologically defined multidrug-resistant Acinetobacter baumannii isolates. J Antimicrob Chemother 2006; 58:1099–1100.

28.

Guo

Zhu

, et al. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005-2014. Clin Microbiol Infect 2016; 22: S9–S14.

29.

Moon

Peck

Chang

, et al. Clinical experience of tigecycline treatment in infections caused by extensively drug-resistant Acinetobacter spp. Microb Drug Resist 2012; 18: 562–566.

30.

Prasad

Sun

Danner

, et al. Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis 2012; 54: 1699–1709

31.

Wang

Pan

Shen

, et al. The efficacy and safety of tigecycline for the treatment of bloodstream infections: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob 2017; 16: 24.