Clinical Experience of Tigecycline Treatment in Infections Caused by Extensively Drug-Resistant Acinetobacter spp.

Abstract

Background: Tigecycline has broad spectrum antimicrobial activity and is approved for complicated intra-abdominal infections, complicated skin and soft tissue infections, and community-acquired pneumonia. There are few data on clinical experience of tigecycline in hospital-acquired pneumonia (HAP) and Acinetobacter spp. infection. Methods: A retrospective study was performed at eight hospitals in Korea from May 2009 to January 2010. Adult patients treated with tigecycline regardless of their source of infection or pathogens were enrolled. Results: Tigecycline was administered in 108 patients. Pneumonia was the most common infection (43.5%), followed by skin and soft tissue infections (20.4%). Acinetobacter baumannii was isolated from 83 patients (76.9%) accounting for 50.3% of isolated pathogens, showing a resistance rate of 67.5% to carbapenems. Superinfection was identified in 32 patients (29.6%). Pseudomonas aeruginosa was most common microorganism causing superinfection (46.9%). Overall 30-day mortality rate was 52.9%. Thirty-day mortality rate of HAP and Acinetobacter spp. infection was 60.5% and 59.4%, respectively. Conclusion: Tigecycline can be considered as an alternative therapy in patients with HAP or infections caused by Acinetobacter spp., especially extensively drug-resistant A. baumannii.

Introduction

Tigecycline is the first antibiotic of a novel class of minocycline derivatives known as the glycylcyclines.¹⁵ It is active against most aerobic, fermentative, and anaerobic Gram-positive- and Gram-negative organisms with the exception of Pseudomonas aeruginosa and some species belonging to the Proteus genera exhibiting significant resistance in vitro.¹⁶ Tigecycline has been approved for the treatment of complicated intra-abdominal infections, complicated skin and soft tissue infections, and community-acquired bacterial pneumonia.^17,21

Even though tigecycline is not yet approved for treatment of hospital-acquired pneumonia (HAP), some studies have evaluated the effectiveness of tigecycline in HAP.^6,11 In one study, tigecycline was noninferior to imipenem in non-ventilator-associated pneumonia (VAP) patients but, in VAP patients, tigecycline showed significantly lower cure rates.¹¹ In contrast, results of a single-arm study suggested that tigecycline could be an acceptable alternative for therapy in patients with VAP.⁷ More clinical data about the efficacy of tigecycline for treatment of HAP or VAP are needed.⁷

Extensively drug-resistant (XDR) Acinetobacter baumannii, which is resistant to most antibiotics including carbapenem, with the exception of colistin, is an increasing problem in nosocomial infections. There are limited therapeutic options for XDR Acinetobacter. Infections caused by XDR Acinetobacter are usually treated with colistin. The use of colistin is frequently complicated by nephrotoxicity. There is no treatment option for pandrug-resistant (PDR) Acinetobacter infection, which is also resistant to colistin. In one study, tigecycline inhibited at least 90% of Acinetobacter spp. isolates evaluated at ≤2 μg/ml, and 95% of those displaying multidrug resistance (MDR).²⁰ The clinical experiences of tigecycline in Acinetobacter infections is limited, with data from only a small number of patients reported thus far.²⁵

Here, we present clinical experience of tigecycline in 108 patients from eight hospitals in Korea. This retrospective study included 84 patients infected by Acinetobacter spp., especially XDR strains.

Methods

Study design and study population

This retrospective study was performed in eight hospitals in Korea from May 1, 2009 to January 31, 2010. Adult patients who were treated with tigecycline were screened. Consecutive patients were enrolled if they were ≥18 years of age and treated with tigecycline for >3 days. Medical records were reviewed to collect demographic data, microbiological data, underlying disease, reasons for tigecycline use, antibiotic treatment, and treatment outcome. Charlson's Comorbidity Index score was calculated to evaluate the severity of the patient's underlying disease.⁸

Definitions

When infection was identified at the time of admission or within 48 hours after admission in a patient who did not fit the criteria for a health care-associated infection, it was defined as community-associated infection. When infection was identified 48 hours or later after admission, or in a patient who was transferred from another hospital, when total duration of inpatient stay was >48 hours, the infection was defined as hospital-acquired infection. A health care-associated infection was defined when infection was identified at the time of admission or within 48 hours after admission in a patient who fulfilled any of the following criteria: (1) intravenous therapy at home, wound care or specialized nursing care or self-administered intravenous medical therapy in the preceding 30 days, (2) hemodialysis or intravenous chemotherapy in the preceding 90 days, (3) admission in an acute care hospital for 2 or more days in the preceding 90 days, and (4) residency in a nursing home or long-term care facility.¹² Sepsis, severe sepsis, and septic shock were defined as described by ACCP/SCCM consensus conference committee.³ When a new isolate was cultured from the patients during tigecycline treatment, it was defined as a superinfection. XDR Acinetobacter spp. was defined as an isolate resistant to all classes of antimicrobial agents—all penicillins and cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems with the exception of colistin. PDR Acinetobacter spp. was defined as being resistant to all antimicrobial agents including colistin. MDR Acinetobacter spp. was defined as resistance to at least three different classes of antibiotics^9,19

Statistical analyses

SPSS for Windows version 11.0 (SPSS, Inc., Chicago, IL) was used for statistical analysis. Student t-test and chi-square test were used for univariate analysis. A p-value<0.05 was considered significant.

Results

A total of 108 patients were enrolled from eight hospitals in Korea. There were more male patients (66.7%) than female patients (33.3%). Mean age of the patients was 61.5±14.9 years (Table 1). Hospital-acquired infections (85.2%) were more common than community-associated- or health care-associated infections (7.4% each). More than half of the patients had indwelling central venous catheters, urinary catheters, or intra-abdominal catheters such as J-P catheters or percutaneous draining tubes. Forty-two patients (38.8%) presented with severe sepsis or septic shock.

Table 1.

Baseline Characteristics of the 108 Patients

	No. of patients (%)
Age, years (median±standard deviation)	61.5±14.9
Sex (male/female)	72/36
Underlying disease
DM	26 (24.1)
HT	32 (29.6)
CKD	18 (16.7)
ARF	15 (13.9)
HD/CRRT	22 (20.4)
Chronic liver disease	10 (9.3)
Malignancy	18 (16.7)
Leukemia	2 (1.9)
Lymphoma	3 (2.8)
Prior antibiotics	48 (44.4)
Prior infection	87 (80.6)
Category of infection
Community-associated	8 (7.4)
Health care-associated	8 (7.4)
Hospital-acquired	92 (85.2)
Central venous catheter	71 (65.7)
Urinary catheter	77 (71.3)
Intra-abdominal catheter	70 (64.8)
Severe sepsis or septic shock	42 (38.8)
Culture negative	7 (6.5)
Polymicrobial infection	49 (45.4)

DM, diabetes mellitus; HT, hypertension; CKD, chronic kidney disease; ARF, acute renal failure; HD, hemodialysis; CRRT, continuous renal replacement therapy.

Pneumonia was the most common cause of infection treated with tigecycline (43.5%) followed by skin and soft tissue infections (20.4%) and complicated intra-abdominal infections (16.7%; Table 2). Among the 53 pneumonia cases, 8 were community-associated, 1 was health-care associated, and 44 cases were HAP including VAP.

Table 2.

Category of Infections Treated with Tigecycline

	No. of patients (%, n=108)
Pneumonia	47 (43.5)
Skin and soft tissue infection	22 (20.4)
Complicated intra-abdominal infection	18 (16.7)
Primary bacteremia	5 (4.6)
Pneumonia and intra-abdominal infection	4 (3.7)
Intra-abdominal infection and SSTI	3 (2.8)
Pneumonia and SSTI	2 (1.9)
Bone and joint infection	3 (2.8)
Others^a	4 (3.7)

One endarteritis, one urinary tract infection, one otitis media, and one intra-abdominal infection with infective endocarditis.

SSTI, skin and soft tissue infection.

A total of 165 isolates were identified in 101 patients. Seven cases (6.5%) were culture negative and 49 cases (45.4%) had polymicrobial infections. Acinetobacter spp. was the most common pathogen (50.3%; Table 3). Acinetobacter spp. was isolated from 83 patients (76.9%). Fifty-six isolates of Acinetobacter spp. were resistant to carbapenems (67.5%). Staphylococcus aureus was the second most common pathogen, accounting for 10.3%, followed by Klebsiella pneumoniae (7.9%), Enterococcus spp. (6.7%), and Escherichia coli (5.5%). P. aeruginosa was isolated from eight patients (4.9%) with polymicrobial infections. These patients were treated with combination antibiotics active against P. aeruginosa.

Table 3.

Etiologic Microorganisms Isolated from 101 out of 108 Patients

	No. (%, n=165)
Acinetobacter spp.	83 (50.3)
Staphylococcus aureus	17 (10.3)
Klebsiella pneumoniae	13 (7.9)
Enterococcus spp.	11 (6.7)
Escherichia coli	9 (5.5)
Stenotrophomonas maltophilia	8 (4.9)
Pseudomonas aeruginosa	8 (4.9)
Enterobacter spp.	5 (3.0)
Others	10 (6.1)

Others: Proteus mirabilis (n=1), Aspergillus spp. (n=1), Candida spp. (n=5), Mycobacterium tuberculosis (n=1), Propionibacterium acnes (n=1), Achromobacter xylosoxidans (n=1).

Superinfection occurred in 32 patients (29.6%). More than one bacterium was cultured in eight patients (25%). P. aeruginosa was the most common isolate of superinfection, accounting for 46.9%, followed by Stenotrophomonas maltophilia (18.8%), Candida spp. (15.6%), and methicillin-resistant Sta. aureus (MRSA; 9.4%) (Table 4). Twenty-six patients were treated for superinfection. Four patients for candiduria and two patients with P. aeruginosa and Ste. maltophilia isolated from sputum were considered to be colonized and were not treated.

Table 4.

Microorganisms Causing Superinfections During Tigecycline Treatment

	No (%, n=32)
Pseudomonas aeruginosa ^a	15 (46.9)
Stenotrophomonas maltophilia ^b	6 (18.8)
Candida spp.	5 (15.6)
Methicillin-resistant Staphylococcus aureus	3 (9.4)
Klebsiella Pneumoinae	2 (6.3)
Enterobacter cloacae	1 (3.1)

Two episodes with Ste. maltophilia, one episode with En. cloacae, one episode with MRSA, and one episode with K. pneumoniae.

One episode with K. pneumoniae, one episode with Staphylococcus epidermidis, one episode with Enterococcus faecalis, and one episode with tuberculosis.

Tigecycline monotherapy was administered in 71 cases (65.7%). Antipseudomonal agents were the most commonly combined antibiotics in patients who received combination therapy. Carbapenems were most commonly combined with tigecycline (20/37, 54.1%), followed by aminoglycoside (4/37, 10.8%) and glycopeptides (3/37, 8.1%).

Overall mortality rate was 37.5% at 14 days and 52.9% at 30 days after tigecycline treatment. Among 83 patients with infections caused by Acinetobacter spp., the 14-day mortality rate was 40.8% and the 30-day mortality rate was 59.4% (Table 5). Patients with pneumonia had a 30-day mortality rate of 60.5%, while patients with complicated intra-abdominal infections had a 30-day mortality rate of 50.0%. Thirty-day mortality rate of patients infected with Acinetobacter spp. and other organisms were 34.6% (9/27) while patients infected with Acinetobacter spp. alone showed 30-day mortality rate of 65.4% (17/37) (p=0.310).

Table 5.

Treatment Outcome of the Patients

	14-Day mortality	p-Value	30-Day mortality	p-Value
Total patients	36/96 (37.5)		46/87 (52.9)
Acinetobacter infections	29/71 (40.8)	0.254	38/64 (59.4)	0.053^a
Non-Acinetobacter infections	7/25 (28.0)		8/23 (34.8)
Pneumonia	19/40 (47.5)	0.122	23/38 (60.5)	0.475^b
Intra-abdominal infections	4/16 (25.0)		8/16 (50.0)

A comparison of 30-day mortality between Acinetobacter infections and non-Acinetobacter infections.

A comparison of 30-day mortality between pneumonia and intra-abdominal infections.

Tigecycline was used in five patients with primary bacteremia. The pathogens from each patient were A. baumannii with methicillin-resistant coagulase negative Staphylococcus, Ste. maltophilia, XDR A. baumannii with extended spectrum β-lactamase producing Es. coli, Sta. aureus with MDR A. baumannii, and XDR A. baumannii. Three out of these five patients showed clinical response and two patients died.

Discussion

In this study, 108 patients were enrolled from eight hospitals in Korea for a 9-month period. Forty-four cases were HAP and Acinetobacter spp. were the most common pathogens, being isolated from 83 patients (76.9%) and accounting for 50.3% of total isolates (83/165). Based on literature review, this study included the largest number of patients with Acinetobacter spp. infections treated with tigecycline by far. We also enrolled the largest number of patients with HAP with the exception of another study.⁶ A study on tigecycline use in cancer patients with serious infections included relatively many cases (110 patients) from a single institution, where MRSA and Enterococcus spp. were the most common pathogens.⁵ Another study on tigecycline use in serious nosocomial infections included 207 patients, in which Enterococcus spp. and Es. coli were the most common pathogens; Acinetobacter spp. accounted for only 12 infections and only 13% were pneumonia.²

In the Latin American Tigecycline Initial Use Registry for VAP (LatinVAP) database, among 117 patients with VAP, Acinetobacter spp. (36 patients) and MRSA were the most common microorganisms isolated.⁶ Patients with APACHE II score ≥15 at admission showed lower clinical success rate and higher mortality rate than those with APACHE II score <15 in the LatinVAP database.⁶

We evaluated mortality rate as an outcome analysis instead of clinical success rate because the latter was difficult to judge in this retrospective study. In this study, the 30-day mortality rate was 52.9% for all patients and 59.4% for patients with infections caused by A. baumannii, which seems to be higher than that in non-Acinetobacter infections but without statistical significance (34.8%, p=0.053, Table 5). In another study, a 30-day mortality rate of 41% was reported among 28 patients with MDR A. baumannii infections treated with tigecycline.¹⁵ A study on the outcome of serious infections with MDR Gram-negative organisms treated with tigecycline showed that 9 patients died among 18 patients,¹ similar to our results. Other studies usually measured clinical success rate instead of mortality rate, which make it difficult to directly compare our result to other studies. Among 110 cases of cancer patients, 36% did not respond to treatment with tigecycline and 36 patients (32.7%) died.⁵ It was reported that a successful clinical outcome of 80% was achieved in patients with infection caused by MDR Gram-negative pathogens following treatment with tigecycline.²² In another study, tigecycline treatment was successful in 73% of serious nosocomial infections.²

There are limited treatment options for infections caused by carbapenem-resistant Acinetobacter spp. The polymyxin antibiotic colistin has been recommended for treatment of XDR Acinetobacter. In one study, polymyxins displayed a clinical efficacy rate of ∼50% to over 80% depending on the particular Acinetobacter infection, appearing to be equal to that of other antibiotics in similar populations.¹⁰ Even though the clinical experience of tigecycline for treatment of XDR Acinetobacter is insufficient, the data including our results suggest that tigecycline could be an alternative option.

In patients with pneumonia in this study, 30-day mortality rate was 60.5%, which was higher than that in intra-abdominal infection (50.0%). Data on outcome of HAP or VAP treated with tigecycline are limited. In a study on cancer patients, clinical response rate of tigecycline in pneumonia was 51%,⁵ which was similar to our result (p>0.05 by chi-square test). In a study on 55 patients of VAP caused by carbapenem-resistant A. baumannii, among 10 patients treated with tigecycline, a clinical success was achieved in 9 patients (90%) in combination with other antibiotics, while clinical responses were achieved in 60.0% of a sulbactam-based regimen, 66.7% of a polymyxin-based regimen, 77.8% of an aminoglycoside-based regimen, and 80.6% of a minocycline-based regimen.⁴ In patients with Gram-negative HAP treated with a 5-day course of antibiotics in the United Kingdom, the critical care mortality rate was 34.2% and in-hospital mortality was 48%.²³ In another study on HAP caused by A. baumannii including 60.3% of MDR isolates, the overall mortality rate was 47.4%.¹⁸ Even though the mortality rate is difficult to compare directly because of the small number of patients enrolled, the mortality rate of HAP treated with tigecycline is not likely to be much higher than those treated with other antibiotics in the literature.

The efficacy of tigecycline in treatment of bacteremia could be suboptimal because the serum concentration of tigecycline is very low. Even though tigecycline is generally safe in the treatment of secondary bacteremia,¹⁴ the use in primary bacteremia is not yet recommended.²⁶ We used tigecycline in five patients with primary bacteremia of XDR A. baumannii, because colistin was not available at that time. Two of the five patients died. Though small, our data also suggest other antimicrobial agents are preferred over tigecycline in treatment of XDR A. baumannii bacteremia, if available. Among uncommon infections, two patients with bone and joint infection were treated with tigecycline and one died. One patient with endarteritis and one with infective endocarditis died.

Tigecycline could cause superinfection of resistant pathogens because it is not active against P. aeruginosa, Proteus spp., and Providencia.^21,24 Superinfections occurred in 32 patients (29.6%) during the study period. P. aeruginosa was the most common microorganism accounting for 46.9% of superinfection. These results are similar to a study reporting diagnosis of superinfections in 23.5% of patients during treatment with tigecycline and P. aeruginosa was the most frequent agent accounting for 58.5% of superinfections including one colonization.¹³

This study has some limitations. First, as it was a retrospective study, we could not determine whether the death of a patient was related to infection or not. In outcome analysis, we could calculate crude mortality only. Second, because this study had no control group of patients, we could not compare the efficacy of tigecycline with other antimicrobial regimen. However, our results were similar to those of other regimens including carbapenems or colistin from studies on the patients with similar infections caused by pathogens susceptible to those antimicrobial agents.

In conclusion, our study suggests tigecycline alone or in combination can be considered as an alternative therapy in patients with HAP or infections caused by Acinetobacter spp. at least in the setting of limited antibiotic options because of MDR. During tigecycline use, special attention should be paid to superinfection caused by microorganisms resistant to tigecycline such as Pseudomonas spp. A large comparative study will be necessary to evaluate the clinical usefulness of tigecycline.

Footnotes

Acknowledgment

This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A102065).

Disclosure Statement

No competing financial interests exist.

References

Anthony

K.B.

, Fishman

N.O.

, Linkin

D.R.

, Gasink

L.B.

, Edelstein

P.H.

, Lautenbach

2008. Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline. Clin. Infect. Dis., 46:567–570.

Bassetti

, Nicolini

, Repetto

, Righi

, Del Bono

, Viscoli

2010. Tigecycline use in serious nosocomial infections: a drug use evaluation. BMC Infect. Dis., 10:287.

Bone

R.C.

, Balk

R.A.

, Cerra

F.B.

, Dellinger

R.P.

, Fein

A.M.

, Knaus

W.A.

, Schein

R.M.

, Sibbald

W.J.

1992. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101:1644–1655.

Chan

J.D.

, Graves

J.A.

, Dellit

T.H.

2010. Antimicrobial treatment and clinical outcomes of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. J. Intensive Care Med., 25:343–348.

Chemaly

R.F.

, Hanmod

S.S.

, Jiang

, Rathod

D.B.

, Mulanovich

, Adachi

J.A.

, Rolston

K.V.

, Raad

I.I.

, Hachem

R.Y.

2009. Tigecycline use in cancer patients with serious infections: a report on 110 cases from a single institution. Medicine (Baltimore), 88:211–220.

Curcio

, Castagnino

, Vazquez

, Vergara

, Curiale

2010. Tigecycline in the treatment of ventilator-associated pneumonia: experience from the Latin American Tigecycline Use Registry. Infez Med., 18:27–34.

Curcio

, Fernandez

, Vergara

, Vazquez

, Luna

C.M.

2009. Late onset ventilator-associated pneumonia due to multidrug-resistant Acinetobacter spp.: experience with tigecycline. J. Chemother., 21:58–62.

Deyo

R.A.

, Cherkin

D.C.

, Ciol

M.A.

1992. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J. Clin. Epidemiol., 45:613–619.

Falagas

M.E.

, Karageorgopoulos

D.E.

2008. Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology. Clin. Infect. Dis., 46:1121–1122author reply 1122.

10.

Fishbain

, Peleg

A.Y.

2010. Treatment of Acinetobacter infections. Clin. Infect. Dis., 51:79–84.

11.

Freire

A.T.

, Melnyk

, Kim

M.J.

, Datsenko

, Dzyublik

, Glumcher

, Chuang

Y.C.

, Maroko

R.T.

, Dukart

, Cooper

C.A.

, Korth-Bradley

J.M.

, Dartois

, Gandjini

2010. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn. Microbiol. Infect. Dis., 68:140–151.

12.

Friedman

N.D.

, Kaye

K.S.

, Stout

J.E.

, McGarry

S.A.

, Trivette

S.L.

, Briggs

J.P.

, Lamm

, Clark

, MacFarquhar

, Walton

A.L.

, Reller

L.B.

, Sexton

D.J.

2002. Health care–associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann. Intern. Med., 137:791–797.

13.

Garcia-Cabrera

, Jimenez-Mejias

M.E.

, Gil Navarro

M.V.

, Gomez-Gomez

M.J.

, Ortiz-Leyba

, Cordero

, Pachon

2010. Superinfection during treatment of nosocomial infections with tigecycline. Eur. J. Clin. Microbiol. Infect. Dis., 29:867–871.

14.

Gardiner

, Dukart

, Cooper

, Babinchak

2010. Safety and efficacy of intravenous tigecycline in subjects with secondary bacteremia: pooled results from 8 phase III clinical trials. Clin. Infect. Dis., 50:229–238.

15.

Gordon

N.C.

, Wareham

D.W.

2009. A review of clinical and microbiological outcomes following treatment of infections involving multidrug-resistant Acinetobacter baumannii with tigecycline. J. Antimicrob. Chemother., 63:775–780.

16.

Hoban

D.J.

, Bouchillon

S.K.

, Johnson

B.M.

, Johnson

J.L.

, Dowzicky

M.J.

2005. In vitro activity of tigecycline against 6792 Gram-negative and Gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004) Diagn. Microbiol. Infect. Dis., 52:215–227.

17.

Tigecycline labeling. www.accessdata.fda.gov/drugsatfda_docs/label/2010/021821s027lbl.pdf. 2011 March 19.

18.

Joung

M.K.

, Kwon

K.T.

, Kang

C.I.

, Cheong

H.S.

, Rhee

J.Y.

, Jung

D.S.

, Chung

S.M.

, Lee

J.A.

, Moon

S.Y.

, Ko

K.S.

, Chung

D.R.

, Lee

N.Y.

, Song

J.H.

, Peck

K.R.

2010. Impact of inappropriate antimicrobial therapy on outcome in patients with hospital-acquired pneumonia caused by Acinetobacter baumannii. J. Infect., 61:212–218.

19.

Manchanda

, Sanchaita

, Singh

2010. Multidrug resistant acinetobacter. J. Glob. Infect. Dis., 2:291–304.

20.

Mendes

R.E.

, Farrell

D.J.

, Sader

H.S.

, Jones

R.N.

2010. Comprehensive assessment of tigecycline activity tested against a worldwide collection of Acinetobacter spp. (2005–2009) Diagn. Microbiol. Infect. Dis., 68:307–311.

21.

Pankey

G.A.

2005. Tigecycline. J. Antimicrob. Chemother., 56:470–480.

22.

Poulakou

, Kontopidou

F.V.

, Paramythiotou

, Kompoti

, Katsiari

, Mainas

, Nicolaou

, Yphantis

, Antoniadou

, Trikka-Graphakos

, Roussou

, Clouva

, Maguina

, Kanellakopoulou

, Armaganidis

, Giamarellou

2009. Tigecycline in the treatment of infections from multi-drug resistant gram-negative pathogens. J. Infect., 58:273–284.

23.

Pugh

R.J.

, Cooke

R.P.

, Dempsey

2010. Short course antibiotic therapy for Gram-negative hospital-acquired pneumonia in the critically ill. J. Hosp. Infect., 74:337–343.

24.

Schafer

J.J.

, Goff

D.A.

2008. Establishing the role of tigecycline in an era of antimicrobial resistance. Expert Rev. Anti Infect. Ther., 6:557–567.

25.

Song

J.Y.

, Cheong

H.J.

, Choi

W.S.

, Heo

J.Y.

, Noh

J.Y.

, Kim

W.J.

2011. Clinical and microbiological characterization of carbapenem-resistant Acinetobacter baumannii bloodstream infections. J. Med. Microbiol., 60:605–611.

26.

Tarchini

2010. Tigecycline and bacteremia–the dangers of post hoc analysis of pooled data. Clin. Infect. Dis., 51:867–868author reply 868.